diff --git a/doc/source/whatsnew/v1.4.0.rst b/doc/source/whatsnew/v1.4.0.rst
index 1f656f267783f..655c875277ea2 100644
--- a/doc/source/whatsnew/v1.4.0.rst
+++ b/doc/source/whatsnew/v1.4.0.rst
@@ -741,6 +741,7 @@ Other
 - Bug in :meth:`Series.to_frame` and :meth:`Index.to_frame` ignoring the ``name`` argument when ``name=None`` is explicitly passed (:issue:`44212`)
 - Bug in :meth:`Series.replace` and :meth:`DataFrame.replace` with ``value=None`` and ExtensionDtypes (:issue:`44270`)
 - Bug in :meth:`FloatingArray.equals` failing to consider two arrays equal if they contain ``np.nan`` values (:issue:`44382`)
+- Bug in :meth:`DataFrame.diff` when passing a NumPy integer object instead of an ``int`` object (:issue:`44572`)
 -
 
 .. ***DO NOT USE THIS SECTION***
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 66d3800301f92..33df7a9f0ac1f 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -8612,8 +8612,12 @@ def melt(
         ),
     )
     def diff(self, periods: int = 1, axis: Axis = 0) -> DataFrame:
-        if not isinstance(periods, int):
-            if not (is_float(periods) and periods.is_integer()):
+        if not lib.is_integer(periods):
+            if not (
+                is_float(periods)
+                # error: "int" has no attribute "is_integer"
+                and periods.is_integer()  # type: ignore[attr-defined]
+            ):
                 raise ValueError("periods must be an integer")
             periods = int(periods)
 
diff --git a/pandas/tests/frame/methods/test_diff.py b/pandas/tests/frame/methods/test_diff.py
index 5fd6928f11f44..fe227db894feb 100644
--- a/pandas/tests/frame/methods/test_diff.py
+++ b/pandas/tests/frame/methods/test_diff.py
@@ -17,6 +17,13 @@ def test_diff_requires_integer(self):
         with pytest.raises(ValueError, match="periods must be an integer"):
             df.diff(1.5)
 
+    def test_diff_allows_np_integer(self):
+        # np.int64 is OK GH#44572
+        df = DataFrame(np.random.randn(2, 2))
+        res = df.diff(np.int64(1))
+        expected = df.diff(1)
+        tm.assert_frame_equal(res, expected)
+
     def test_diff(self, datetime_frame):
         the_diff = datetime_frame.diff(1)