diff --git a/doc/source/whatsnew/v1.3.2.rst b/doc/source/whatsnew/v1.3.2.rst
index 4e6ea85e2ff1d..bcb096e630d85 100644
--- a/doc/source/whatsnew/v1.3.2.rst
+++ b/doc/source/whatsnew/v1.3.2.rst
@@ -33,6 +33,8 @@ Bug fixes
 - Bug in :meth:`pandas.read_excel` modifies the dtypes dictionary when reading a file with duplicate columns (:issue:`42462`)
 - 1D slices over extension types turn into N-dimensional slices over ExtensionArrays (:issue:`42430`)
 - :meth:`.Styler.hide_columns` now hides the index name header row as well as column headers (:issue:`42101`)
+- Bug in de-serializing datetime indexes in PYTHONOPTIMIZED mode (:issue:`42866`)
+-
 
 .. ---------------------------------------------------------------------------
 
diff --git a/pandas/core/indexes/datetimes.py b/pandas/core/indexes/datetimes.py
index fbfee9a1f524c..ff9a273267306 100644
--- a/pandas/core/indexes/datetimes.py
+++ b/pandas/core/indexes/datetimes.py
@@ -92,7 +92,8 @@ def _new_DatetimeIndex(cls, d):
                 # These are already stored in our DatetimeArray; if they are
                 #  also in the pickle and don't match, we have a problem.
                 if key in d:
-                    assert d.pop(key) == getattr(dta, key)
+                    assert d[key] == getattr(dta, key)
+                    d.pop(key)
         result = cls._simple_new(dta, **d)
     else:
         with warnings.catch_warnings():
diff --git a/pandas/tests/test_downstream.py b/pandas/tests/test_downstream.py
index ea95f90d3a2cb..e34ca9e7f9e27 100644
--- a/pandas/tests/test_downstream.py
+++ b/pandas/tests/test_downstream.py
@@ -69,6 +69,21 @@ def test_oo_optimizable():
     subprocess.check_call([sys.executable, "-OO", "-c", "import pandas"])
 
 
+def test_oo_optimized_datetime_index_unpickle():
+    # GH 42866
+    subprocess.check_call(
+        [
+            sys.executable,
+            "-OO",
+            "-c",
+            (
+                "import pandas as pd, pickle; "
+                "pickle.loads(pickle.dumps(pd.date_range('2021-01-01', periods=1)))"
+            ),
+        ]
+    )
+
+
 @tm.network
 # Cython import warning
 @pytest.mark.filterwarnings("ignore:pandas.util.testing is deprecated")