diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 1c139f4692b52..b83f317814ad9 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -92,7 +92,7 @@ Other API changes
 
 Deprecations
 ~~~~~~~~~~~~
--
+- Deprecated accepting slices in :meth:`DataFrame.take`, call ``obj[slicer]`` or pass a sequence of integers instead (:issue:`51539`)
 -
 
 .. ---------------------------------------------------------------------------
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 4a6b95f9a2e11..10e64f7fbd52c 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -3749,6 +3749,9 @@ def __getitem__(self, key):
         if getattr(indexer, "dtype", None) == bool:
             indexer = np.where(indexer)[0]
 
+        if isinstance(indexer, slice):
+            return self._slice(indexer, axis=1)
+
         data = self._take_with_is_copy(indexer, axis=1)
 
         if is_single_key:
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 7c2e42ef71d46..33dc62564d34e 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -3910,6 +3910,14 @@ class  max_speed
                 "not slice."
             )
         else:
+            warnings.warn(
+                # GH#51539
+                f"Passing a slice to {type(self).__name__}.take is deprecated "
+                "and will raise in a future version. Use `obj[slicer]` or pass "
+                "a sequence of integers instead.",
+                FutureWarning,
+                stacklevel=find_stack_level(),
+            )
             # We can get here with a slice via DataFrame.__getitem__
             indices = np.arange(
                 indices.start, indices.stop, indices.step, dtype=np.intp
diff --git a/pandas/tests/frame/indexing/test_take.py b/pandas/tests/frame/indexing/test_take.py
index a3d13ecd7b98e..8c17231440917 100644
--- a/pandas/tests/frame/indexing/test_take.py
+++ b/pandas/tests/frame/indexing/test_take.py
@@ -4,6 +4,16 @@
 
 
 class TestDataFrameTake:
+    def test_take_slices_deprecated(self, float_frame):
+        # GH#51539
+        df = float_frame
+
+        slc = slice(0, 4, 1)
+        with tm.assert_produces_warning(FutureWarning):
+            df.take(slc, axis=0)
+        with tm.assert_produces_warning(FutureWarning):
+            df.take(slc, axis=1)
+
     def test_take(self, float_frame):
         # homogeneous
         order = [3, 1, 2, 0]