diff --git a/CHANGES.rst b/CHANGES.rst
index 12d89870..a181badc 100644
--- a/CHANGES.rst
+++ b/CHANGES.rst
@@ -7,6 +7,7 @@ Unreleased
 
 -   Inline some optional imports that are only used for certain CLI
     commands. :pr:`4606`
+-   Relax type annotation for ``after_request`` functions. :issue:`4600`
 
 
 Version 2.1.2
diff --git a/src/flask/typing.py b/src/flask/typing.py
index a839a7e4..ec7c7969 100644
--- a/src/flask/typing.py
+++ b/src/flask/typing.py
@@ -4,7 +4,7 @@ import typing as t
 if t.TYPE_CHECKING:
     from _typeshed.wsgi import WSGIApplication  # noqa: F401
     from werkzeug.datastructures import Headers  # noqa: F401
-    from werkzeug.wrappers.response import Response  # noqa: F401
+    from werkzeug.wrappers import Response  # noqa: F401
 
 # The possible types that are directly convertible or are a Response object.
 ResponseValue = t.Union[
@@ -35,8 +35,13 @@ ResponseReturnValue = t.Union[
     "WSGIApplication",
 ]
 
+# Allow any subclass of werkzeug.Response, such as the one from Flask,
+# as a callback argument. Using werkzeug.Response directly makes a
+# callback annotated with flask.Response fail type checking.
+ResponseClass = t.TypeVar("ResponseClass", bound="Response")
+
 AppOrBlueprintKey = t.Optional[str]  # The App key is None, whereas blueprints are named
-AfterRequestCallable = t.Callable[["Response"], "Response"]
+AfterRequestCallable = t.Callable[[ResponseClass], ResponseClass]
 BeforeFirstRequestCallable = t.Callable[[], None]
 BeforeRequestCallable = t.Callable[[], t.Optional[ResponseReturnValue]]
 TeardownCallable = t.Callable[[t.Optional[BaseException]], None]