diff --git a/mypy/checkexpr.py b/mypy/checkexpr.py
index 9990caaeb7a1..bef88b135429 100644
--- a/mypy/checkexpr.py
+++ b/mypy/checkexpr.py
@@ -6748,8 +6748,55 @@ def any_causes_overload_ambiguity(
                 for formal in formals:
                     matching_formals.append(matched_callable.arg_types[formal])
             if not all_same_types(matching_formals) and not all_same_types(matching_returns):
-                # Any maps to multiple different types, and the return types of these items differ.
+                if _any_in_unrelated_position(get_proper_type(arg_type), matching_formals):
+                    continue
+                return True
+    return False
+
+
+def _any_in_unrelated_position(arg_type: ProperType, formals: list[Type]) -> bool:
+    """Whether Any in arg_type doesn't affect overload differentiation."""
+    if isinstance(arg_type, AnyType):
+        return False
+
+    proper_formals = [get_proper_type(f) for f in formals]
+    if len(proper_formals) < 2:
+        return False
+
+    if isinstance(arg_type, TupleType):
+        if not all(
+            isinstance(f, TupleType) and len(f.items) == len(arg_type.items)
+            for f in proper_formals
+        ):
+            return False
+        tuple_formals = cast(list[TupleType], proper_formals)
+        for i, item in enumerate(arg_type.items):
+            item_proper = get_proper_type(item)
+            if has_any_type(item_proper):
+                formal_items = [tf.items[i] for tf in tuple_formals]
+                if all_same_types(formal_items):
+                    continue
+                if not _any_in_unrelated_position(item_proper, formal_items):
+                    return False
+        return True
+
+    if isinstance(arg_type, CallableType):
+        if not all(isinstance(f, CallableType) for f in proper_formals):
+            return False
+        formal_callables = cast(list[CallableType], proper_formals)
+        first_args = formal_callables[0].arg_types
+        for fc in formal_callables[1:]:
+            if len(fc.arg_types) != len(first_args):
+                return False
+            for a1, a2 in zip(first_args, fc.arg_types):
+                if not is_same_type(a1, a2):
+                    return False
+        return_types = [fc.ret_type for fc in formal_callables]
+        for candidate in return_types:
+            if all(is_subtype(candidate, other) for other in return_types):
                 return True
+        return False
+
     return False
 
 
diff --git a/test-data/unit/check-overloading.test b/test-data/unit/check-overloading.test
index 68eccb46ab21..8d8017a37a3d 100644
--- a/test-data/unit/check-overloading.test
+++ b/test-data/unit/check-overloading.test
@@ -1906,6 +1906,73 @@ a: Any
 reveal_type(f(a))     # N: Revealed type is "def (*Any, **Any) -> Any"
 reveal_type(f(a)(a))  # N: Revealed type is "Any"
 
+[case testOverloadWithNestedAnyInCallableDoesNotCauseAmbiguity]
+# https://github.com/python/mypy/issues/20442
+from typing import overload, Any, Generic, Callable
+from typing_extensions import TypeVar
+
+T = TypeVar("T")
+
+class MyClass(Generic[T]):
+    pass
+
+class Result1:
+    pass
+
+class Result2:
+    pass
+
+@overload
+def test(x: Callable[[MyClass[Any]], int]) -> Result1: ...
+@overload
+def test(x: Callable[[MyClass[Any]], Any]) -> Result2: ...
+def test(x: object) -> object:
+    return x
+
+def fn1(c: MyClass[Any]) -> int:
+    return 1
+
+reveal_type(test(fn1))  # N: Revealed type is "__main__.Result1"
+[builtins fixtures/tuple.pyi]
+
+[case testOverloadWithNestedAnyInTupleCallableDoesNotCauseAmbiguity]
+# https://github.com/python/mypy/issues/20442
+from typing import overload, Any, Generic, Callable, Iterable
+from collections.abc import Hashable
+from typing_extensions import TypeVar, Self
+
+IndexT0 = TypeVar("IndexT0")
+T = TypeVar("T")
+
+class Series:
+    pass
+
+class _LocIndexerFrame(Generic[T]):
+    @overload
+    def __getitem__(self, idx: tuple[Callable[[DataFrame], int], str]) -> int: ...
+    @overload
+    def __getitem__(self, idx: tuple[Callable[[DataFrame], list[Hashable]], str]) -> Series: ...
+    @overload
+    def __getitem__(self, idx: tuple[Callable[[DataFrame], Any], Iterable[Hashable]]) -> T: ...
+    def __getitem__(self, idx: object) -> object:
+        return idx
+
+class DataFrame(Generic[IndexT0]):
+    @property
+    def loc(self) -> _LocIndexerFrame[Self]:
+        return _LocIndexerFrame()
+
+def select2(df: DataFrame[Any]) -> list[Hashable]:
+    return []
+
+def select3(_: DataFrame[Any]) -> int:
+    return 1
+
+reveal_type(DataFrame().loc[select2, "x"])  # N: Revealed type is "__main__.Series"
+reveal_type(DataFrame().loc[select3, "x"])  # N: Revealed type is "builtins.int"
+[builtins fixtures/property.pyi]
+[typing fixtures/typing-full.pyi]
+
 [case testOverloadOnOverloadWithType]
 from typing import Any, Type, TypeVar, overload
 from mod import MyInt