diff --git a/Lib/test/pickletester.py b/Lib/test/pickletester.py
index 75e2afa7ae68df0..dafd2e9717b5b0c 100644
--- a/Lib/test/pickletester.py
+++ b/Lib/test/pickletester.py
@@ -4906,6 +4906,14 @@ def test_clear_pickler_memo(self):
             self.assertNotEqual(first_pickled, second_pickled)
             self.assertEqual(first_pickled, third_pickled)
 
+    def test_clear_unpickler_memo(self):
+        value = [b'repeated'] * 2
+        data = pickle.dumps(value, protocol=4)
+        unpickler = self.unpickler_class(io.BytesIO(data * 2))
+        self.assertEqual(unpickler.load(), value)
+        unpickler.memo.clear()
+        self.assertEqual(unpickler.load(), value)
+
     def test_priming_pickler_memo(self):
         # Verify that we can set the Pickler's memo attribute.
         data = ["abcdefg", "abcdefg", 44]
diff --git a/Lib/test/test_pickle.py b/Lib/test/test_pickle.py
index 9d86c1b050304db..475c52cd6c1f477 100644
--- a/Lib/test/test_pickle.py
+++ b/Lib/test/test_pickle.py
@@ -17,6 +17,7 @@
 from test import support
 from test.support import cpython_only, import_helper, os_helper
 from test.support.import_helper import ensure_lazy_imports
+from test.support.script_helper import assert_python_ok
 
 from test.pickletester import AbstractHookTests
 from test.pickletester import AbstractUnpickleTests
@@ -455,6 +456,70 @@ class CPicklerUnpicklerObjectTests(AbstractPicklerUnpicklerObjectTests, unittest
         pickler_class = _pickle.Pickler
         unpickler_class = _pickle.Unpickler
 
+        @support.requires_subprocess()
+        def test_clear_unpickler_memo_memory_error(self):
+            import_helper.import_module('_testcapi')
+            code = dedent('''
+                import _testcapi
+                import io
+                import pickle
+                from test.support import SuppressCrashReport
+
+                value = [b'repeated'] * 2
+                data = pickle.dumps(value, protocol=4)
+                unpickler = pickle.Unpickler(io.BytesIO(data * 2))
+                assert unpickler.load() == value
+                memo = unpickler.memo.copy()
+                clear = unpickler.memo.clear
+                reset = _testcapi.remove_mem_hooks
+                failed = False
+                with SuppressCrashReport():
+                    # Fail the replacement memo allocation, with all callable
+                    # lookups performed before enabling the allocator hook.
+                    _testcapi.set_nomemory(0, 1)
+                    try:
+                        clear()
+                    except MemoryError:
+                        failed = True
+                    finally:
+                        reset()
+                    assert failed
+                    assert unpickler.memo.copy() == memo
+                    clear()
+                    assert unpickler.memo.copy() == {}
+                    assert unpickler.load() == value
+            ''')
+            assert_python_ok('-c', code)
+
+        @support.requires_subprocess()
+        def test_clear_unpickler_memo_reentrant(self):
+            code = dedent(r'''
+                import io
+                import pickle
+                from test.support import gc_collect, SuppressCrashReport
+
+                snapshots = []
+                class Entry:
+                    def __del__(self):
+                        snapshots.append(unpickler.memo.copy())
+
+                value = [b'repeated'] * 2
+                # Create the entry through the C unpickler so clearing its
+                # sole reference runs the finalizer even without the GIL.
+                data = b'\x80\x02c__main__\nEntry\n)\x81q\x00.'
+                unpickler = pickle.Unpickler(
+                    io.BytesIO(data + pickle.dumps(value, protocol=4)))
+                unpickler.load()
+                gc_collect()
+                with SuppressCrashReport():
+                    unpickler.memo.clear()
+                    gc_collect()
+                    assert snapshots == [{}]
+                    assert unpickler.memo.copy() == {}
+                    assert unpickler.load() == value
+            ''')
+            assert_python_ok('-c', code)
+
         def test_issue18339(self):
             unpickler = self.unpickler_class(io.BytesIO())
             with self.assertRaises(TypeError):
diff --git a/Misc/NEWS.d/next/Library/2026-10-22-03-55-33.gh-issue-159739.a8bf30.rst b/Misc/NEWS.d/next/Library/2026-10-22-03-55-33.gh-issue-159739.a8bf30.rst
new file mode 100644
index 000000000000000..79aea931e201c6a
--- /dev/null
+++ b/Misc/NEWS.d/next/Library/2026-10-22-03-55-33.gh-issue-159739.a8bf30.rst
@@ -0,0 +1,3 @@
+Fix clearing a :class:`pickle.Unpickler` memo so that the unpickler can be
+reused for independent records. Preserve a valid memo if allocation fails or
+releasing an old entry runs a destructor that accesses the memo.
diff --git a/Modules/_pickle.c b/Modules/_pickle.c
index cba47396a7c2806..ecfbc19749cbe26 100644
--- a/Modules/_pickle.c
+++ b/Modules/_pickle.c
@@ -1675,16 +1675,16 @@ _Unpickler_NewMemo(Py_ssize_t new_size)
     return memo;
 }
 
-/* Free the unpickler's memo, taking care to decref any items left in it. */
+/* Replace the unpickler's memo and release the old entries. */
 static void
-_Unpickler_MemoCleanup(UnpicklerObject *self)
+_Unpickler_MemoCleanup(UnpicklerObject *self, PyObject **replacement)
 {
     Py_ssize_t i;
     PyObject **memo = self->memo;
 
-    if (self->memo == NULL)
+    self->memo = replacement;
+    if (memo == NULL)
         return;
-    self->memo = NULL;
     i = self->memo_size;
     while (--i >= 0) {
         Py_XDECREF(memo[i]);
@@ -7465,7 +7465,7 @@ Unpickler_clear(PyObject *op)
         self->buffer.buf = NULL;
     }
 
-    _Unpickler_MemoCleanup(self);
+    _Unpickler_MemoCleanup(self, NULL);
     PyMem_Free(self->marks);
     self->marks = NULL;
     PyMem_Free(self->input_line);
@@ -7611,10 +7611,13 @@ static PyObject *
 _pickle_UnpicklerMemoProxy_clear_impl(UnpicklerMemoProxyObject *self)
 /*[clinic end generated code: output=d20cd43f4ba1fb1f input=b1df7c52e7afd9bd]*/
 {
-    _Unpickler_MemoCleanup(self->unpickler);
-    self->unpickler->memo = _Unpickler_NewMemo(self->unpickler->memo_size);
-    if (self->unpickler->memo == NULL)
+    UnpicklerObject *unpickler = self->unpickler;
+    PyObject **memo = _Unpickler_NewMemo(unpickler->memo_size);
+    if (memo == NULL) {
         return NULL;
+    }
+    unpickler->memo_len = 0;
+    _Unpickler_MemoCleanup(unpickler, memo);
     Py_RETURN_NONE;
 }
 
@@ -7827,7 +7830,7 @@ Unpickler_set_memo(PyObject *op, PyObject *obj, void *Py_UNUSED(closure))
         return -1;
     }
 
-    _Unpickler_MemoCleanup(self);
+    _Unpickler_MemoCleanup(self, NULL);
     self->memo_size = new_memo_size;
     self->memo = new_memo;