diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 92124a536fe26..db46b82ab90ac 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -301,6 +301,7 @@ Performance improvements
 - Performance improvement in :class:`Series` reductions (:issue:`52341`)
 - Performance improvement in :func:`concat` when ``axis=1`` and objects have different indexes (:issue:`52541`)
 - Performance improvement in :meth:`.DataFrameGroupBy.groups` (:issue:`53088`)
+- Performance improvement in :meth:`DataFrame.isin` for extension dtypes (:issue:`53514`)
 - Performance improvement in :meth:`DataFrame.loc` when selecting rows and columns (:issue:`53014`)
 - Performance improvement in :meth:`Series.add` for pyarrow string and binary dtypes (:issue:`53150`)
 - Performance improvement in :meth:`Series.corr` and :meth:`Series.cov` for extension dtypes (:issue:`52502`)
@@ -310,6 +311,7 @@ Performance improvements
 - Performance improvement in :meth:`~arrays.ArrowExtensionArray.to_numpy` (:issue:`52525`)
 - Performance improvement when doing various reshaping operations on :class:`arrays.IntegerArrays` & :class:`arrays.FloatingArray` by avoiding doing unnecessary validation (:issue:`53013`)
 - Performance improvement when indexing with pyarrow timestamp and duration dtypes (:issue:`53368`)
+-
 
 .. ---------------------------------------------------------------------------
 .. _whatsnew_210.bug_fixes:
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index d4c2124182ea5..1524197938a81 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -11731,15 +11731,21 @@ def isin(self, values: Series | DataFrame | Sequence | Mapping) -> DataFrame:
                     "to be passed to DataFrame.isin(), "
                     f"you passed a '{type(values).__name__}'"
                 )
-            # error: Argument 2 to "isin" has incompatible type "Union[Sequence[Any],
-            # Mapping[Any, Any]]"; expected "Union[Union[ExtensionArray,
-            # ndarray[Any, Any]], Index, Series]"
-            res_values = algorithms.isin(
-                self.values.ravel(),
-                values,  # type: ignore[arg-type]
-            )
+
+            def isin_(x):
+                # error: Argument 2 to "isin" has incompatible type "Union[Series,
+                # DataFrame, Sequence[Any], Mapping[Any, Any]]"; expected
+                # "Union[Union[Union[ExtensionArray, ndarray[Any, Any]], Index,
+                # Series], List[Any], range]"
+                result = algorithms.isin(
+                    x.ravel(),
+                    values,  # type: ignore[arg-type]
+                )
+                return result.reshape(x.shape)
+
+            res_values = self._mgr.apply(isin_)
             result = self._constructor(
-                res_values.reshape(self.shape),
+                res_values,
                 self.index,
                 self.columns,
                 copy=False,
diff --git a/pandas/tests/frame/methods/test_isin.py b/pandas/tests/frame/methods/test_isin.py
index e924963f588f3..b4511aad27a93 100644
--- a/pandas/tests/frame/methods/test_isin.py
+++ b/pandas/tests/frame/methods/test_isin.py
@@ -217,3 +217,11 @@ def test_isin_read_only(self):
         result = df.isin(arr)
         expected = DataFrame([True, True, True])
         tm.assert_frame_equal(result, expected)
+
+    def test_isin_not_lossy(self):
+        # GH 53514
+        val = 1666880195890293744
+        df = DataFrame({"a": [val], "b": [1.0]})
+        result = df.isin([val])
+        expected = DataFrame({"a": [True], "b": [False]})
+        tm.assert_frame_equal(result, expected)