diff --git a/pandas/_libs/free_threading_config.pxi.in b/pandas/_libs/free_threading_config.pxi.in
new file mode 100644
index 0000000000000..fe7ca399389ab
--- /dev/null
+++ b/pandas/_libs/free_threading_config.pxi.in
@@ -0,0 +1,3 @@
+# Autogenerated file containing Cython compile-time defines
+
+DEF CYTHON_COMPATIBLE_WITH_FREE_THREADING = @freethreading_compatible@
diff --git a/pandas/_libs/internals.pyx b/pandas/_libs/internals.pyx
index 4f0c2892f5a58..8caf7e5fb99b2 100644
--- a/pandas/_libs/internals.pyx
+++ b/pandas/_libs/internals.pyx
@@ -4,10 +4,7 @@ cimport cython
 from cpython.object cimport PyObject
 from cpython.pyport cimport PY_SSIZE_T_MAX
 from cpython.slice cimport PySlice_GetIndicesEx
-from cpython.weakref cimport (
-    PyWeakref_GetObject,
-    PyWeakref_NewRef,
-)
+from cpython.weakref cimport PyWeakref_NewRef
 from cython cimport Py_ssize_t
 
 import numpy as np
@@ -29,6 +26,14 @@ from pandas._libs.util cimport (
     is_integer_object,
 )
 
+include "free_threading_config.pxi"
+
+IF CYTHON_COMPATIBLE_WITH_FREE_THREADING:
+    from cpython.ref cimport Py_DECREF
+    from cpython.weakref cimport PyWeakref_GetRef
+ELSE:
+    from cpython.weakref cimport PyWeakref_GetObject
+
 
 cdef extern from "Python.h":
     PyObject* Py_None
@@ -908,17 +913,37 @@ cdef class BlockValuesRefs:
         # if force=False. Clearing for every insertion causes slowdowns if
         # all these objects stay alive, e.g. df.items() for wide DataFrames
         # see GH#55245 and GH#55008
+        IF CYTHON_COMPATIBLE_WITH_FREE_THREADING:
+            cdef PyObject* pobj
+            cdef bint status
+
         if force or len(self.referenced_blocks) > self.clear_counter:
-            self.referenced_blocks = [
-                ref for ref in self.referenced_blocks
-                if PyWeakref_GetObject(ref) != Py_None
-            ]
+            IF CYTHON_COMPATIBLE_WITH_FREE_THREADING:
+                new_referenced_blocks = []
+                for ref in self.referenced_blocks:
+                    status = PyWeakref_GetRef(ref, &pobj)
+                    if status == -1:
+                        return
+                    elif status == 1:
+                        new_referenced_blocks.append(ref)
+                        Py_DECREF(<object>pobj)
+                self.referenced_blocks = new_referenced_blocks
+            ELSE:
+                self.referenced_blocks = [
+                    ref for ref in self.referenced_blocks
+                    if PyWeakref_GetObject(ref) != Py_None
+                ]
+
             nr_of_refs = len(self.referenced_blocks)
             if nr_of_refs < self.clear_counter // 2:
                 self.clear_counter = max(self.clear_counter // 2, 500)
             elif nr_of_refs > self.clear_counter:
                 self.clear_counter = max(self.clear_counter * 2, nr_of_refs)
 
+    cpdef _add_reference_maybe_locked(self, Block blk):
+        self._clear_dead_references()
+        self.referenced_blocks.append(PyWeakref_NewRef(blk, None))
+
     cpdef add_reference(self, Block blk):
         """Adds a new reference to our reference collection.
 
@@ -927,8 +952,15 @@ cdef class BlockValuesRefs:
         blk : Block
             The block that the new references should point to.
         """
+        IF CYTHON_COMPATIBLE_WITH_FREE_THREADING:
+            with cython.critical_section(self):
+                self._add_reference_maybe_locked(blk)
+        ELSE:
+            self._add_reference_maybe_locked(blk)
+
+    def _add_index_reference_maybe_locked(self, index: object) -> None:
         self._clear_dead_references()
-        self.referenced_blocks.append(PyWeakref_NewRef(blk, None))
+        self.referenced_blocks.append(PyWeakref_NewRef(index, None))
 
     def add_index_reference(self, index: object) -> None:
         """Adds a new reference to our reference collection when creating an index.
@@ -938,8 +970,16 @@ cdef class BlockValuesRefs:
         index : Index
             The index that the new reference should point to.
         """
-        self._clear_dead_references()
-        self.referenced_blocks.append(PyWeakref_NewRef(index, None))
+        IF CYTHON_COMPATIBLE_WITH_FREE_THREADING:
+            with cython.critical_section(self):
+                self._add_index_reference_maybe_locked(index)
+        ELSE:
+            self._add_index_reference_maybe_locked(index)
+
+    def _has_reference_maybe_locked(self) -> bool:
+        self._clear_dead_references(force=True)
+        # Checking for more references than block pointing to itself
+        return len(self.referenced_blocks) > 1
 
     def has_reference(self) -> bool:
         """Checks if block has foreign references.
@@ -951,6 +991,8 @@ cdef class BlockValuesRefs:
         -------
         bool
         """
-        self._clear_dead_references(force=True)
-        # Checking for more references than block pointing to itself
-        return len(self.referenced_blocks) > 1
+        IF CYTHON_COMPATIBLE_WITH_FREE_THREADING:
+            with cython.critical_section(self):
+                return self._has_reference_maybe_locked()
+        ELSE:
+            return self._has_reference_maybe_locked()
diff --git a/pandas/_libs/meson.build b/pandas/_libs/meson.build
index 5fb6f1118d648..a50976767928a 100644
--- a/pandas/_libs/meson.build
+++ b/pandas/_libs/meson.build
@@ -50,6 +50,19 @@ _khash_primitive_helper_dep = declare_dependency(
     sources: _khash_primitive_helper,
 )
 
+cdata = configuration_data()
+if cy.version().version_compare('>=3.1.0')
+    cdata.set('freethreading_compatible', '1')
+else
+    cdata.set('freethreading_compatible', '0')
+endif
+_free_threading_config = configure_file(
+    input: 'free_threading_config.pxi.in',
+    output: 'free_threading_config.pxi',
+    configuration: cdata,
+    install: false,
+)
+
 subdir('tslibs')
 
 libs_sources = {