diff --git a/doc/source/admin/galaxy_options.rst b/doc/source/admin/galaxy_options.rst
index a86b3a410e3..de6cfdb0961 100644
--- a/doc/source/admin/galaxy_options.rst
+++ b/doc/source/admin/galaxy_options.rst
@@ -1885,6 +1885,17 @@
 :Type: str
 
 
+~~~~~~~~~~~~~~~~~~~~~
+``galaxy_url_prefix``
+~~~~~~~~~~~~~~~~~~~~~
+
+:Description:
+    URL prefix for Galaxy application. If Galaxy should be served
+    under a prefix set this to the desired prefix value.
+:Default: ``/``
+:Type: str
+
+
 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
 ``galaxy_infrastructure_url``
 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
@@ -1946,7 +1957,7 @@
 
 :Description:
     The brand image source.
-:Default: ``/static/favicon.png``
+:Default: ``static/favicon.png``
 :Type: str
 
 
diff --git a/lib/galaxy/config/sample/galaxy.yml.sample b/lib/galaxy/config/sample/galaxy.yml.sample
index aacdb8a7100..bad8e33a111 100644
--- a/lib/galaxy/config/sample/galaxy.yml.sample
+++ b/lib/galaxy/config/sample/galaxy.yml.sample
@@ -993,6 +993,10 @@ galaxy:
   # user_preferences_extra_conf.yml
   #default_locale: auto
 
+  # URL prefix for Galaxy application. If Galaxy should be served under
+  # a prefix set this to the desired prefix value.
+  #galaxy_url_prefix: /
+
   # URL (with schema http/https) of the Galaxy instance as accessible
   # within your local network - if specified used as a default by pulsar
   # file staging and Jupyter Docker container for communicating back
@@ -1020,7 +1024,7 @@ galaxy:
   #logo_url: /
 
   # The brand image source.
-  #logo_src: /static/favicon.png
+  #logo_src: static/favicon.png
 
   # The custom brand image source.
   #logo_src_secondary: null
diff --git a/lib/galaxy/web/framework/middleware/static.py b/lib/galaxy/web/framework/middleware/static.py
deleted file mode 100644
index fcc878f16ff..00000000000
--- a/lib/galaxy/web/framework/middleware/static.py
+++ /dev/null
@@ -1,64 +0,0 @@
-import os
-from typing import List, Tuple
-
-from paste import request
-from paste.fileapp import FileApp
-from paste.httpheaders import ETAG
-from paste.urlparser import StaticURLParser
-
-
-class CacheableStaticURLParser(StaticURLParser):
-
-    def __init__(self, directory, cache_seconds=None, directory_per_host=None):
-        StaticURLParser.__init__(self, directory)
-        self.cache_seconds = cache_seconds
-        self.directory_per_host = directory_per_host
-
-    def __call__(self, environ, start_response):
-        path_info = environ.get('PATH_INFO', '')
-        if not path_info:
-            # See if this is a static file hackishly mapped.
-            if os.path.exists(self.directory) and os.path.isfile(self.directory):
-                app = FileApp(self.directory)
-                if self.cache_seconds:
-                    app.cache_control(max_age=int(self.cache_seconds))
-                return app(environ, start_response)
-            return self.add_slash(environ, start_response)
-        if path_info == '/':
-            # @@: This should obviously be configurable
-            filename = 'index.html'
-        else:
-            filename = request.path_info_pop(environ)
-
-        directory = self.directory
-        host = environ.get('HTTP_HOST')
-        if self.directory_per_host and host:
-            for host_key, host_val in self.directory_per_host.items():
-                if host_key in host:
-                    directory = host_val
-                    break
-
-        full = os.path.join(directory, filename)
-        if not os.path.exists(full):
-            return self.not_found(environ, start_response)
-        if os.path.isdir(full):
-            # @@: Cache?
-            return self.__class__(full)(environ, start_response)
-        if environ.get('PATH_INFO') and environ.get('PATH_INFO') != '/':
-            return self.error_extra_path(environ, start_response)
-        if_none_match = environ.get('HTTP_IF_NONE_MATCH')
-        if if_none_match:
-            mytime = os.stat(full).st_mtime
-            if str(mytime) == if_none_match:
-                headers: List[Tuple[str, str]] = []
-                ETAG.update(headers, mytime)
-                start_response('304 Not Modified', headers)
-                return ['']  # empty body
-        app = FileApp(full)
-        if self.cache_seconds:
-            app.cache_control(max_age=int(self.cache_seconds))
-        return app(environ, start_response)
-
-
-def make_static(global_conf, document_root, cache_seconds=None):
-    return CacheableStaticURLParser(document_root, cache_seconds)
diff --git a/lib/galaxy/webapps/base/webapp.py b/lib/galaxy/webapps/base/webapp.py
index 1b0e87aa6d0..dbe2a93fd3b 100644
--- a/lib/galaxy/webapps/base/webapp.py
+++ b/lib/galaxy/webapps/base/webapp.py
@@ -976,36 +976,3 @@ def build_native_uwsgi_app(paste_factory, config_section):
     app_kwds = get_app_kwds(config_section)
     uwsgi_app = paste_factory({}, load_app_kwds=app_kwds)
     return uwsgi_app
-
-
-def build_url_map(app, global_conf, local_conf):
-    from paste.urlmap import URLMap
-    from galaxy.web.framework.middleware.static import CacheableStaticURLParser as Static
-    urlmap = URLMap()
-    # Merge the global and local configurations
-    conf = global_conf.copy()
-    conf.update(local_conf)
-    # Get cache time in seconds
-    cache_time = conf.get("static_cache_time", None)
-    if cache_time is not None:
-        cache_time = int(cache_time)
-    # Send to dynamic app by default
-    urlmap["/"] = app
-
-    def get_static_from_config(option_name, default_path):
-        config_val = conf.get(option_name, default_url_path(default_path))
-        per_host_config_option = f"{option_name}_by_host"
-        per_host_config = conf.get(per_host_config_option)
-        return Static(config_val, cache_time, directory_per_host=per_host_config)
-
-    # Define static mappings from config
-    urlmap["/static"] = get_static_from_config("static_dir", "static/")
-    urlmap["/images"] = get_static_from_config("static_images_dir", "static/images")
-    urlmap["/static/scripts"] = get_static_from_config("static_scripts_dir", "static/scripts/")
-    urlmap["/static/welcome.html"] = get_static_from_config("static_welcome_html", "static/welcome.html")
-    urlmap["/favicon.ico"] = get_static_from_config("static_favicon_dir", "static/favicon.ico")
-    urlmap["/robots.txt"] = get_static_from_config("static_robots_txt", "static/robots.txt")
-
-    if 'static_local_dir' in conf:
-        urlmap["/static_local"] = Static(conf["static_local_dir"], cache_time)
-    return urlmap, cache_time
diff --git a/lib/galaxy/webapps/galaxy/buildapp.py b/lib/galaxy/webapps/galaxy/buildapp.py
index df934b3aac9..10a8c52bffa 100644
--- a/lib/galaxy/webapps/galaxy/buildapp.py
+++ b/lib/galaxy/webapps/galaxy/buildapp.py
@@ -207,10 +207,6 @@ def app_pair(global_conf, load_app_kwds=None, wsgi_preflight=True, **kwargs):
     # Wrap the webapp in some useful middleware
     if kwargs.get('middleware', True):
         webapp = wrap_in_middleware(webapp, global_conf, app.application_stack, **kwargs)
-    if asbool(kwargs.get('static_enabled', True)):
-        webapp = wrap_if_allowed(webapp, app.application_stack, wrap_in_static,
-                                 args=(global_conf,),
-                                 kwargs=dict(plugin_frameworks=[app.visualizations_registry], **kwargs))
     app.application_stack.register_postfork_function(postfork_setup)
 
     for th in threading.enumerate():
@@ -1399,8 +1395,3 @@ def wrap_in_middleware(app, global_conf, application_stack, **local_conf):
         from galaxy.web.framework.middleware.sqldebug import SQLDebugMiddleware
         app = wrap_if_allowed(app, stack, SQLDebugMiddleware, args=(webapp, {}))
     return app
-
-
-def wrap_in_static(app, global_conf, plugin_frameworks=None, **local_conf):
-    urlmap, cache_time = galaxy.webapps.base.webapp.build_url_map(app, global_conf, local_conf)
-    return urlmap
diff --git a/lib/galaxy/webapps/galaxy/config_schema.yml b/lib/galaxy/webapps/galaxy/config_schema.yml
index 3d745236733..3ae5458e5f0 100644
--- a/lib/galaxy/webapps/galaxy/config_schema.yml
+++ b/lib/galaxy/webapps/galaxy/config_schema.yml
@@ -1361,6 +1361,14 @@ mapping:
           Users can override this settings in their user preferences if the localization
           settings are enabled in user_preferences_extra_conf.yml
 
+      galaxy_url_prefix:
+        type: str
+        default: '/'
+        required: false
+        desc: |
+          URL prefix for Galaxy application. If Galaxy should be served under a prefix set this to
+          the desired prefix value.
+
       galaxy_infrastructure_url:
         type: str
         default: http://localhost:8080
@@ -1409,7 +1417,7 @@ mapping:
 
       logo_src:
         type: str
-        default: /static/favicon.png
+        default: static/favicon.png
         required: false
         per_host: true
         desc: |
diff --git a/lib/galaxy/webapps/galaxy/fast_app.py b/lib/galaxy/webapps/galaxy/fast_app.py
index 27051feccc6..2c81dd6a961 100644
--- a/lib/galaxy/webapps/galaxy/fast_app.py
+++ b/lib/galaxy/webapps/galaxy/fast_app.py
@@ -1,13 +1,23 @@
+import os
+import stat
+import typing
 from pathlib import Path
 from typing import cast
 
+import anyio
 from fastapi import FastAPI, Request
 from fastapi.middleware.wsgi import WSGIMiddleware
+from fastapi.staticfiles import StaticFiles
+from starlette.datastructures import Headers
+from starlette.exceptions import HTTPException
 from starlette.middleware.cors import CORSMiddleware
 from starlette.responses import (
     FileResponse,
+    RedirectResponse,
     Response,
 )
+from starlette.staticfiles import PathLike
+from starlette.types import Scope
 
 from galaxy.webapps.base.api import (
     add_exception_handler,
@@ -16,6 +26,8 @@ from galaxy.webapps.base.api import (
 )
 from galaxy.webapps.base.webapp import config_allows_origin
 
+if typing.TYPE_CHECKING:
+    from galaxy.config import Configuration
 
 # https://fastapi.tiangolo.com/tutorial/metadata/#metadata-for-tags
 api_tags_metadata = [
@@ -58,6 +70,90 @@ api_tags_metadata = [
 ]
 
 
+def get_static_from_config(conf, option_name, default_path):
+    config_val = conf.get(option_name, default_path)
+    per_host_config_option = f"{option_name}_by_host"
+    per_host_config = conf.get(per_host_config_option)
+    return (config_val, per_host_config or {})
+
+
+class GalaxyStaticFiles(StaticFiles):
+    def __init__(
+        self, *, config: "Configuration", html: bool = False, check_dir: bool = True
+    ) -> None:
+        self.config = config
+        self.directory, self.directory_per_host = get_static_from_config(
+            config, "static_dir", "static/"
+        )
+        super().__init__(
+            directory=self.directory, packages=None, html=html, check_dir=check_dir
+        )
+
+    def get_directories(
+        self, directory: PathLike = None, packages: typing.List[str] = None
+    ) -> typing.List[PathLike]:
+        pass
+
+    async def check_config(self) -> None:
+        """
+        Perform a one-off configuration check that GalaxyStaticFiles is actually
+        pointed at directories, so that we can raise loud errors rather than
+        just returning 404 responses.
+        """
+        for directory in (self.directory, *self.directory_per_host.values()):
+            try:
+                stat_result = await anyio.to_thread.run_sync(os.stat, directory)
+            except FileNotFoundError:
+                raise RuntimeError(
+                    f"StaticFiles directory '{directory}' does not exist."
+                )
+            if not (
+                stat.S_ISDIR(stat_result.st_mode) or stat.S_ISLNK(stat_result.st_mode)
+            ):
+                raise RuntimeError(
+                    f"StaticFiles path '{directory}' is not a directory."
+                )
+
+    async def get_response(self, path: str, scope: Scope) -> Response:
+        """
+        Returns an HTTP response, given the incoming path, method and request headers.
+        """
+        if scope["method"] not in ("GET", "HEAD"):
+            raise HTTPException(status_code=405)
+
+        headers = Headers(scope=scope)
+
+        try:
+            full_path, stat_result = await anyio.to_thread.run_sync(
+                self.lookup_path, path, headers.get("host")
+            )
+        except PermissionError:
+            raise HTTPException(status_code=401)
+        except OSError:
+            raise
+
+        if stat_result and stat.S_ISREG(stat_result.st_mode):
+            # We have a static file to serve.
+            return self.file_response(full_path, stat_result, scope)
+
+        raise HTTPException(status_code=404)
+
+    def lookup_path(
+        self, path: str, host: typing.Optional[str] = None
+    ) -> typing.Tuple[str, typing.Optional[os.stat_result]]:
+        directory = self.directory_per_host.get(host, self.directory)
+        full_path = os.path.realpath(os.path.join(directory, path))
+        directory = os.path.realpath(directory)
+        if os.path.commonprefix([full_path, directory]) != directory:
+            # Don't allow misbehaving clients to break out of the static files
+            # directory.
+            return "", None
+        try:
+            return full_path, os.stat(full_path)
+        except (FileNotFoundError, NotADirectoryError):
+            return "", None
+
+
 class GalaxyCORSMiddleware(CORSMiddleware):
 
     def __init__(self, *args, **kwds):
@@ -129,6 +225,16 @@ def initialize_fast_app(gx_wsgi_webapp, gx_app):
     add_galaxy_middleware(app, gx_app)
     add_request_id_middleware(app)
     include_all_package_routers(app, 'galaxy.webapps.galaxy.api')
+    app.mount("/static", GalaxyStaticFiles(config=gx_app.config), name="static")
+
+    @app.get("/favicon.ico")
+    async def favicon():
+        return RedirectResponse(url="static/favicon.ico")
+
     wsgi_handler = WSGIMiddleware(gx_wsgi_webapp)
     app.mount('/', wsgi_handler)
+    if gx_app.config.galaxy_url_prefix != '/':
+        parent_app = FastAPI()
+        parent_app.mount(gx_app.config.galaxy_url_prefix, app=app)
+        return parent_app
     return app
diff --git a/lib/galaxy/webapps/reports/buildapp.py b/lib/galaxy/webapps/reports/buildapp.py
index 4b8098ea813..86508116077 100644
--- a/lib/galaxy/webapps/reports/buildapp.py
+++ b/lib/galaxy/webapps/reports/buildapp.py
@@ -68,10 +68,6 @@ def app_factory(global_conf, load_app_kwds=None, **kwargs):
     # Wrap the webapp in some useful middleware
     if kwargs.get('middleware', True):
         webapp = wrap_in_middleware(webapp, global_conf, app.application_stack, **kwargs)
-    if asbool(kwargs.get('static_enabled', True)):
-        webapp = wrap_if_allowed(webapp, app.application_stack, wrap_in_static,
-                                 args=(global_conf,),
-                                 kwargs=kwargs)
     return webapp
 
 
@@ -121,10 +117,5 @@ def wrap_in_middleware(app, global_conf, application_stack, **local_conf):
     return app
 
 
-def wrap_in_static(app, global_conf, **local_conf):
-    urlmap, _ = galaxy.webapps.base.webapp.build_url_map(app, global_conf, local_conf)
-    return urlmap
-
-
 def uwsgi_app():
     return galaxy.webapps.base.webapp.build_native_uwsgi_app(app_factory, "reports")
diff --git a/lib/tool_shed/webapp/buildapp.py b/lib/tool_shed/webapp/buildapp.py
index 65affaf8d81..48ab3dee0ac 100644
--- a/lib/tool_shed/webapp/buildapp.py
+++ b/lib/tool_shed/webapp/buildapp.py
@@ -190,10 +190,6 @@ def app_factory(global_conf, load_app_kwds=None, **kwargs):
     # Wrap the webapp in some useful middleware
     if kwargs.get('middleware', True):
         webapp = wrap_in_middleware(webapp, global_conf, app.application_stack, **kwargs)
-    if asbool(kwargs.get('static_enabled', True)):
-        webapp = wrap_if_allowed(webapp, app.application_stack, wrap_in_static,
-                                 args=(global_conf,),
-                                 kwargs=kwargs)
     return webapp
 
 
@@ -263,11 +259,6 @@ def wrap_in_middleware(app, global_conf, application_stack, **local_conf):
     return app
 
 
-def wrap_in_static(app, global_conf, **local_conf):
-    urlmap, _ = galaxy.webapps.base.webapp.build_url_map(app, global_conf, local_conf)
-    return urlmap
-
-
 def _map_redirects(mapper):
     """
     Add redirect to the Routes mapper and forward the received query string.