diff --git a/newsfragments/4420.bugfix.rst b/newsfragments/4420.bugfix.rst
new file mode 100644
index 0000000000..c5f75fcddb
--- /dev/null
+++ b/newsfragments/4420.bugfix.rst
@@ -0,0 +1,2 @@
+Raises an exception when ``py_limited_api`` is used in a build with
+``Py_GIL_DISABLED``. This is currently not supported (python/cpython#111506).
diff --git a/setuptools/command/bdist_wheel.py b/setuptools/command/bdist_wheel.py
index eca5568aad..8f06786659 100644
--- a/setuptools/command/bdist_wheel.py
+++ b/setuptools/command/bdist_wheel.py
@@ -274,10 +274,7 @@ def finalize_options(self) -> None:
             self.distribution.has_ext_modules() or self.distribution.has_c_libraries()
         )
 
-        if self.py_limited_api and not re.match(
-            PY_LIMITED_API_PATTERN, self.py_limited_api
-        ):
-            raise ValueError(f"py-limited-api must match '{PY_LIMITED_API_PATTERN}'")
+        self._validate_py_limited_api()
 
         # Support legacy [wheel] section for setting universal
         wheel = self.distribution.get_option_dict("wheel")
@@ -291,6 +288,21 @@ def finalize_options(self) -> None:
         if self.build_number is not None and not self.build_number[:1].isdigit():
             raise ValueError("Build tag (build-number) must start with a digit.")
 
+    def _validate_py_limited_api(self) -> None:
+        if not self.py_limited_api:
+            return
+
+        if not re.match(PY_LIMITED_API_PATTERN, self.py_limited_api):
+            raise ValueError(f"py-limited-api must match '{PY_LIMITED_API_PATTERN}'")
+
+        if sysconfig.get_config_var("Py_GIL_DISABLED"):
+            raise ValueError(
+                f"`py_limited_api={self.py_limited_api!r}` not supported. "
+                "`Py_LIMITED_API` is currently incompatible with "
+                f"`Py_GIL_DISABLED` ({sys.abiflags=!r}). "
+                "See https://github.com/python/cpython/issues/111506."
+            )
+
     @property
     def wheel_dist_name(self) -> str:
         """Return distribution full name with - replaced with _"""