diff --git a/mypy/erasetype.py b/mypy/erasetype.py
index b41eefcd4821..5d95b221af15 100644
--- a/mypy/erasetype.py
+++ b/mypy/erasetype.py
@@ -34,6 +34,7 @@
     get_proper_type,
     get_proper_types,
 )
+from mypy.typevartuples import erased_vars
 
 
 def erase_type(typ: Type) -> ProperType:
@@ -77,17 +78,7 @@ def visit_deleted_type(self, t: DeletedType) -> ProperType:
         return t
 
     def visit_instance(self, t: Instance) -> ProperType:
-        args: list[Type] = []
-        for tv in t.type.defn.type_vars:
-            # Valid erasure for *Ts is *tuple[Any, ...], not just Any.
-            if isinstance(tv, TypeVarTupleType):
-                args.append(
-                    UnpackType(
-                        tv.tuple_fallback.copy_modified(args=[AnyType(TypeOfAny.special_form)])
-                    )
-                )
-            else:
-                args.append(AnyType(TypeOfAny.special_form))
+        args = erased_vars(t.type.defn.type_vars, TypeOfAny.special_form)
         return Instance(t.type, args, t.line)
 
     def visit_type_var(self, t: TypeVarType) -> ProperType:
diff --git a/mypy/nodes.py b/mypy/nodes.py
index d215bcfce098..2eb39d4baaf6 100644
--- a/mypy/nodes.py
+++ b/mypy/nodes.py
@@ -3165,9 +3165,6 @@ def add_type_vars(self) -> None:
                     self.type_var_tuple_prefix = i
                     self.type_var_tuple_suffix = len(self.defn.type_vars) - i - 1
                 self.type_vars.append(vd.name)
-        assert not (
-            self.has_param_spec_type and self.has_type_var_tuple_type
-        ), "Mixing type var tuples and param specs not supported yet"
 
     @property
     def name(self) -> str:
diff --git a/mypy/semanal_typeargs.py b/mypy/semanal_typeargs.py
index dbf5136afa1b..646bb28a3b6e 100644
--- a/mypy/semanal_typeargs.py
+++ b/mypy/semanal_typeargs.py
@@ -39,6 +39,7 @@
     get_proper_types,
     split_with_prefix_and_suffix,
 )
+from mypy.typevartuples import erased_vars
 
 
 class TypeArgumentAnalyzer(MixedTraverserVisitor):
@@ -89,7 +90,14 @@ def visit_type_alias_type(self, t: TypeAliasType) -> None:
             return
         self.seen_aliases.add(t)
         assert t.alias is not None, f"Unfixed type alias {t.type_ref}"
-        is_error = self.validate_args(t.alias.name, tuple(t.args), t.alias.alias_tvars, t)
+        is_error, is_invalid = self.validate_args(
+            t.alias.name, tuple(t.args), t.alias.alias_tvars, t
+        )
+        if is_invalid:
+            # If there is an arity error (e.g. non-Parameters used for ParamSpec etc.),
+            # then it is safer to erase the arguments completely, to avoid crashes later.
+            # TODO: can we move this logic to typeanal.py?
+            t.args = erased_vars(t.alias.alias_tvars, TypeOfAny.from_error)
         if not is_error:
             # If there was already an error for the alias itself, there is no point in checking
             # the expansion, most likely it will result in the same kind of error.
@@ -113,7 +121,9 @@ def visit_instance(self, t: Instance) -> None:
         info = t.type
         if isinstance(info, FakeInfo):
             return  # https://github.com/python/mypy/issues/11079
-        self.validate_args(info.name, t.args, info.defn.type_vars, t)
+        _, is_invalid = self.validate_args(info.name, t.args, info.defn.type_vars, t)
+        if is_invalid:
+            t.args = tuple(erased_vars(info.defn.type_vars, TypeOfAny.from_error))
         if t.type.fullname == "builtins.tuple" and len(t.args) == 1:
             # Normalize Tuple[*Tuple[X, ...], ...] -> Tuple[X, ...]
             arg = t.args[0]
@@ -125,7 +135,7 @@ def visit_instance(self, t: Instance) -> None:
 
     def validate_args(
         self, name: str, args: tuple[Type, ...], type_vars: list[TypeVarLikeType], ctx: Context
-    ) -> bool:
+    ) -> tuple[bool, bool]:
         if any(isinstance(v, TypeVarTupleType) for v in type_vars):
             prefix = next(i for (i, v) in enumerate(type_vars) if isinstance(v, TypeVarTupleType))
             tvt = type_vars[prefix]
@@ -136,10 +146,11 @@ def validate_args(
             args = start + (TupleType(list(middle), tvt.tuple_fallback),) + end
 
         is_error = False
+        is_invalid = False
         for (i, arg), tvar in zip(enumerate(args), type_vars):
             if isinstance(tvar, TypeVarType):
                 if isinstance(arg, ParamSpecType):
-                    is_error = True
+                    is_invalid = True
                     self.fail(
                         INVALID_PARAM_SPEC_LOCATION.format(format_type(arg, self.options)),
                         ctx,
@@ -152,7 +163,7 @@ def validate_args(
                     )
                     continue
                 if isinstance(arg, Parameters):
-                    is_error = True
+                    is_invalid = True
                     self.fail(
                         f"Cannot use {format_type(arg, self.options)} for regular type variable,"
                         " only for ParamSpec",
@@ -205,13 +216,16 @@ def validate_args(
                 if not isinstance(
                     get_proper_type(arg), (ParamSpecType, Parameters, AnyType, UnboundType)
                 ):
+                    is_invalid = True
                     self.fail(
                         "Can only replace ParamSpec with a parameter types list or"
                         f" another ParamSpec, got {format_type(arg, self.options)}",
                         ctx,
                         code=codes.VALID_TYPE,
                     )
-        return is_error
+        if is_invalid:
+            is_error = True
+        return is_error, is_invalid
 
     def visit_unpack_type(self, typ: UnpackType) -> None:
         super().visit_unpack_type(typ)
diff --git a/mypy/typevars.py b/mypy/typevars.py
index 3d74a40c303f..e871973104a2 100644
--- a/mypy/typevars.py
+++ b/mypy/typevars.py
@@ -3,7 +3,6 @@
 from mypy.erasetype import erase_typevars
 from mypy.nodes import TypeInfo
 from mypy.types import (
-    AnyType,
     Instance,
     ParamSpecType,
     ProperType,
@@ -15,6 +14,7 @@
     TypeVarType,
     UnpackType,
 )
+from mypy.typevartuples import erased_vars
 
 
 def fill_typevars(typ: TypeInfo) -> Instance | TupleType:
@@ -64,16 +64,7 @@ def fill_typevars(typ: TypeInfo) -> Instance | TupleType:
 
 def fill_typevars_with_any(typ: TypeInfo) -> Instance | TupleType:
     """Apply a correct number of Any's as type arguments to a type."""
-    args: list[Type] = []
-    for tv in typ.defn.type_vars:
-        # Valid erasure for *Ts is *tuple[Any, ...], not just Any.
-        if isinstance(tv, TypeVarTupleType):
-            args.append(
-                UnpackType(tv.tuple_fallback.copy_modified(args=[AnyType(TypeOfAny.special_form)]))
-            )
-        else:
-            args.append(AnyType(TypeOfAny.special_form))
-    inst = Instance(typ, args)
+    inst = Instance(typ, erased_vars(typ.defn.type_vars, TypeOfAny.special_form))
     if typ.tuple_type is None:
         return inst
     erased_tuple_type = erase_typevars(typ.tuple_type, {tv.id for tv in typ.defn.type_vars})
diff --git a/mypy/typevartuples.py b/mypy/typevartuples.py
index af2effbd4035..2a9998c10746 100644
--- a/mypy/typevartuples.py
+++ b/mypy/typevartuples.py
@@ -5,9 +5,12 @@
 from typing import Sequence
 
 from mypy.types import (
+    AnyType,
     Instance,
     ProperType,
     Type,
+    TypeVarLikeType,
+    TypeVarTupleType,
     UnpackType,
     get_proper_type,
     split_with_prefix_and_suffix,
@@ -30,3 +33,14 @@ def extract_unpack(types: Sequence[Type]) -> ProperType | None:
         if isinstance(types[0], UnpackType):
             return get_proper_type(types[0].type)
     return None
+
+
+def erased_vars(type_vars: Sequence[TypeVarLikeType], type_of_any: int) -> list[Type]:
+    args: list[Type] = []
+    for tv in type_vars:
+        # Valid erasure for *Ts is *tuple[Any, ...], not just Any.
+        if isinstance(tv, TypeVarTupleType):
+            args.append(UnpackType(tv.tuple_fallback.copy_modified(args=[AnyType(type_of_any)])))
+        else:
+            args.append(AnyType(type_of_any))
+    return args
diff --git a/test-data/unit/check-typevar-tuple.test b/test-data/unit/check-typevar-tuple.test
index ea692244597c..f49e1b3c6613 100644
--- a/test-data/unit/check-typevar-tuple.test
+++ b/test-data/unit/check-typevar-tuple.test
@@ -2460,3 +2460,30 @@ def test(x: T, *args: Unpack[Ts]) -> Tuple[T, Unpack[Ts]]: ...
 
 reveal_type(test)  # N: Revealed type is "def [T, Ts] (builtins.list[T`2], *args: Unpack[Ts`-2]) -> __main__.CM[Tuple[T`2, Unpack[Ts`-2]]]"
 [builtins fixtures/tuple.pyi]
+
+[case testMixingTypeVarTupleAndParamSpec]
+from typing import Generic, ParamSpec, TypeVarTuple, Unpack, Callable, TypeVar
+
+P = ParamSpec("P")
+Ts = TypeVarTuple("Ts")
+
+class A(Generic[P, Unpack[Ts]]): ...
+class B(Generic[Unpack[Ts], P]): ...
+
+a: A[[int, str], int, str]
+reveal_type(a)  # N: Revealed type is "__main__.A[[builtins.int, builtins.str], builtins.int, builtins.str]"
+b: B[int, str, [int, str]]
+reveal_type(b)  # N: Revealed type is "__main__.B[builtins.int, builtins.str, [builtins.int, builtins.str]]"
+
+x: A[int, str, [int, str]]  # E: Can only replace ParamSpec with a parameter types list or another ParamSpec, got "int"
+reveal_type(x)  # N: Revealed type is "__main__.A[Any, Unpack[builtins.tuple[Any, ...]]]"
+y: B[[int, str], int, str]  # E: Can only replace ParamSpec with a parameter types list or another ParamSpec, got "str"
+reveal_type(y)  # N: Revealed type is "__main__.B[Unpack[builtins.tuple[Any, ...]], Any]"
+
+R = TypeVar("R")
+class C(Generic[P, R]):
+    fn: Callable[P, None]
+
+c: C[int, str]  # E: Can only replace ParamSpec with a parameter types list or another ParamSpec, got "int"
+reveal_type(c.fn)  # N: Revealed type is "def (*Any, **Any)"
+[builtins fixtures/tuple.pyi]