diff --git a/mypy/meet.py b/mypy/meet.py
index bfc6d88a1e209..6f48b8f186232 100644
--- a/mypy/meet.py
+++ b/mypy/meet.py
@@ -348,6 +348,23 @@ def are_related_types(
         )
 
 
+def _type_form_item_can_be_union(item: Type) -> bool:
+    """Can a value of TypeForm[item] be an instance of types.UnionType?
+
+    A type expression is a types.UnionType instance at runtime exactly when it
+    is a union expression such as `int | str`.
+    """
+    item = get_proper_type(item)
+    if isinstance(item, (AnyType, UnionType)):
+        return True
+    if isinstance(item, TypeVarType):
+        if item.values:
+            return any(_type_form_item_can_be_union(v) for v in item.values)
+        # An unconstrained type variable can be bound to a union.
+        return True
+    return False
+
+
 def is_overlapping_types(
     left: Type,
     right: Type,
@@ -522,6 +539,18 @@ def _type_object_overlap(left: Type, right: Type) -> bool:
             # 1. Type[C] vs Callable[..., C] overlap even if the latter is not class object.
             if isinstance(left, TypeType) and isinstance(right, CallableType):
                 return _is_overlapping_types(left.item, right.ret_type)
+            # 2b. TypeForm[T] vs types.UnionType: a type expression like `int | str`
+            # is an instance of types.UnionType at runtime, so e.g.
+            # `isinstance(t, UnionType)` where `t: TypeForm[Any]` can be true.
+            # (Checked before case 2 below, which would otherwise return False.)
+            if (
+                isinstance(left, TypeType)
+                and left.is_type_form
+                and isinstance(right, Instance)
+                and right.type.fullname == "types.UnionType"
+                and _type_form_item_can_be_union(left.item)
+            ):
+                return True
             # 2. Type[C] vs Meta, where Meta is a metaclass for C.
             if isinstance(left, TypeType) and isinstance(right, Instance):
                 if isinstance(left.item, Instance):
diff --git a/test-data/unit/check-typeform.test b/test-data/unit/check-typeform.test
index d08826e233f76..826d9c412a00e 100644
--- a/test-data/unit/check-typeform.test
+++ b/test-data/unit/check-typeform.test
@@ -808,3 +808,28 @@ from typing import Optional, TypeForm
 typx: TypeForm = Optional  # E: Incompatible types in assignment (expression has type "int", variable has type "TypeForm[Any]")
 [builtins fixtures/primitives.pyi]
 [typing fixtures/typing-full.pyi]
+
+
+-- isinstance() with types.UnionType and TypeForm (see #21910)
+
+[case testTypeFormIsinstanceUnionType]
+# flags: --warn-unreachable
+from types import UnionType
+from typing import Any
+from typing_extensions import TypeForm
+
+def f(t: TypeForm[Any]) -> None:
+    if isinstance(t, UnionType):
+        reveal_type(t)  # N: Revealed type is "types.UnionType"
+    else:
+        reveal_type(t)  # N: Revealed type is "TypeForm[Any]"
+
+def g(t: TypeForm[int | str]) -> None:
+    if isinstance(t, UnionType):
+        reveal_type(t)  # N: Revealed type is "types.UnionType"
+
+def h(t: TypeForm[int]) -> None:
+    if isinstance(t, UnionType):
+        pass  # E: Statement is unreachable
+[builtins fixtures/isinstance_python3_10.pyi]
+[typing fixtures/typing-full.pyi]