diff --git a/doc/source/whatsnew/v1.4.0.rst b/doc/source/whatsnew/v1.4.0.rst
index 8608dffd58090..c441de3c21159 100644
--- a/doc/source/whatsnew/v1.4.0.rst
+++ b/doc/source/whatsnew/v1.4.0.rst
@@ -229,6 +229,7 @@ Missing
 
 MultiIndex
 ^^^^^^^^^^
+- Bug in :meth:`MultiIndex.get_loc` where the first level is a :class:`DatetimeIndex` and a string key is passed (:issue:`42465`)
 - Bug in :meth:`MultiIndex.reindex` when passing a ``level`` that corresponds to an ``ExtensionDtype`` level (:issue:`42043`)
 -
 
diff --git a/pandas/core/indexes/multi.py b/pandas/core/indexes/multi.py
index c9144f311c25d..684f23b41568b 100644
--- a/pandas/core/indexes/multi.py
+++ b/pandas/core/indexes/multi.py
@@ -3160,10 +3160,12 @@ def convert_indexer(start, stop, step, indexer=indexer, codes=level_codes):
             if level > 0 or self._lexsort_depth == 0:
                 # Desired level is not sorted
                 if isinstance(idx, slice):
+                    # test_get_loc_partial_timestamp_multiindex
                     locs = (level_codes >= idx.start) & (level_codes < idx.stop)
                     return locs
 
                 locs = np.array(level_codes == idx, dtype=bool, copy=False)
+
                 if not locs.any():
                     # The label is present in self.levels[level] but unused:
                     raise KeyError(key)
diff --git a/pandas/tests/indexes/multi/test_partial_indexing.py b/pandas/tests/indexes/multi/test_partial_indexing.py
index fb34fc7f570ba..47efc43d5eae0 100644
--- a/pandas/tests/indexes/multi/test_partial_indexing.py
+++ b/pandas/tests/indexes/multi/test_partial_indexing.py
@@ -1,3 +1,4 @@
+import numpy as np
 import pytest
 
 from pandas import (
@@ -45,6 +46,42 @@ def test_partial_string_matching_single_index(df):
         tm.assert_frame_equal(result, expected)
 
 
+def test_get_loc_partial_timestamp_multiindex(df):
+    mi = df.index
+    key = ("2016-01-01", "a")
+    loc = mi.get_loc(key)
+
+    expected = np.zeros(len(mi), dtype=bool)
+    expected[[0, 3]] = True
+    tm.assert_numpy_array_equal(loc, expected)
+
+    key2 = ("2016-01-02", "a")
+    loc2 = mi.get_loc(key2)
+    expected2 = np.zeros(len(mi), dtype=bool)
+    expected2[[6, 9]] = True
+    tm.assert_numpy_array_equal(loc2, expected2)
+
+    key3 = ("2016-01", "a")
+    loc3 = mi.get_loc(key3)
+    expected3 = np.zeros(len(mi), dtype=bool)
+    expected3[mi.get_level_values(1).get_loc("a")] = True
+    tm.assert_numpy_array_equal(loc3, expected3)
+
+    key4 = ("2016", "a")
+    loc4 = mi.get_loc(key4)
+    expected4 = expected3
+    tm.assert_numpy_array_equal(loc4, expected4)
+
+    # non-monotonic
+    taker = np.arange(len(mi), dtype=np.intp)
+    taker[::2] = taker[::-2]
+    mi2 = mi.take(taker)
+    loc5 = mi2.get_loc(key)
+    expected5 = np.zeros(len(mi2), dtype=bool)
+    expected5[[3, 14]] = True
+    tm.assert_numpy_array_equal(loc5, expected5)
+
+
 def test_partial_string_timestamp_multiindex(df):
     # GH10331
     df_swap = df.swaplevel(0, 1).sort_index()
diff --git a/pandas/tests/indexing/multiindex/test_loc.py b/pandas/tests/indexing/multiindex/test_loc.py
index 13ddf6f7d71db..104fa2da7a67e 100644
--- a/pandas/tests/indexing/multiindex/test_loc.py
+++ b/pandas/tests/indexing/multiindex/test_loc.py
@@ -745,6 +745,19 @@ def test_get_loc_datetime_index():
     assert mi.get_loc("2001-01") == slice(0, 31, None)
     assert index.get_loc("2001-01") == slice(0, 31, None)
 
+    loc = mi[::2].get_loc("2001-01")
+    expected = index[::2].get_loc("2001-01")
+    assert loc == expected
+
+    loc = mi.repeat(2).get_loc("2001-01")
+    expected = index.repeat(2).get_loc("2001-01")
+    assert loc == expected
+
+    loc = mi.append(mi).get_loc("2001-01")
+    expected = index.append(index).get_loc("2001-01")
+    # TODO: standardize return type for MultiIndex.get_loc
+    tm.assert_numpy_array_equal(loc.nonzero()[0], expected)
+
 
 def test_loc_setitem_indexer_differently_ordered():
     # GH#34603