diff --git a/doc/source/whatsnew/v1.2.0.rst b/doc/source/whatsnew/v1.2.0.rst
index 1236c672a1fa1..c854f995bd2ea 100644
--- a/doc/source/whatsnew/v1.2.0.rst
+++ b/doc/source/whatsnew/v1.2.0.rst
@@ -266,6 +266,7 @@ Deprecations
 - Deprecated indexing :class:`DataFrame` rows with datetime-like strings ``df[string]``, use ``df.loc[string]`` instead (:issue:`36179`)
 - Deprecated casting an object-dtype index of ``datetime`` objects to :class:`DatetimeIndex` in the :class:`Series` constructor (:issue:`23598`)
 - Deprecated :meth:`Index.is_all_dates` (:issue:`27744`)
+- Deprecated automatic alignment on comparison operations between :class:`DataFrame` and :class:`Series`, do ``frame, ser = frame.align(ser, axis=1, copy=False)`` before e.g. ``frame == ser`` (:issue:`28759`)
 - :meth:`Rolling.count` with ``min_periods=None`` will default to the size of the window in a future version (:issue:`31302`)
 
 .. ---------------------------------------------------------------------------
diff --git a/pandas/core/ops/__init__.py b/pandas/core/ops/__init__.py
index f92f67e1d03d7..36e3a0e37c1ae 100644
--- a/pandas/core/ops/__init__.py
+++ b/pandas/core/ops/__init__.py
@@ -5,6 +5,7 @@
 """
 import operator
 from typing import TYPE_CHECKING, Optional, Set, Type
+import warnings
 
 import numpy as np
 
@@ -488,6 +489,18 @@ def to_series(right):
     elif isinstance(right, ABCSeries):
         # axis=1 is default for DataFrame-with-Series op
         axis = left._get_axis_number(axis) if axis is not None else 1
+
+        if not flex:
+            if not left.axes[axis].equals(right.index):
+                warnings.warn(
+                    "Automatic reindexing on DataFrame vs Series comparisons "
+                    "is deprecated and will raise ValueError in a future version.  "
+                    "Do `left, right = left.align(right, axis=1, copy=False)` "
+                    "before e.g. `left == right`",
+                    FutureWarning,
+                    stacklevel=3,
+                )
+
         left, right = left.align(
             right, join="outer", axis=axis, level=level, copy=False
         )
diff --git a/pandas/tests/arithmetic/test_datetime64.py b/pandas/tests/arithmetic/test_datetime64.py
index 626dd4f748e0b..46be296759088 100644
--- a/pandas/tests/arithmetic/test_datetime64.py
+++ b/pandas/tests/arithmetic/test_datetime64.py
@@ -318,11 +318,16 @@ def test_dt64arr_timestamp_equality(self, box_with_array):
         expected = tm.box_expected([False, True], xbox)
         tm.assert_equal(result, expected)
 
-        result = ser != ser[0]
+        warn = FutureWarning if box_with_array is pd.DataFrame else None
+        with tm.assert_produces_warning(warn):
+            # alignment for frame vs series comparisons deprecated
+            result = ser != ser[0]
         expected = tm.box_expected([False, True], xbox)
         tm.assert_equal(result, expected)
 
-        result = ser != ser[1]
+        with tm.assert_produces_warning(warn):
+            # alignment for frame vs series comparisons deprecated
+            result = ser != ser[1]
         expected = tm.box_expected([True, True], xbox)
         tm.assert_equal(result, expected)
 
@@ -330,11 +335,15 @@ def test_dt64arr_timestamp_equality(self, box_with_array):
         expected = tm.box_expected([True, False], xbox)
         tm.assert_equal(result, expected)
 
-        result = ser == ser[0]
+        with tm.assert_produces_warning(warn):
+            # alignment for frame vs series comparisons deprecated
+            result = ser == ser[0]
         expected = tm.box_expected([True, False], xbox)
         tm.assert_equal(result, expected)
 
-        result = ser == ser[1]
+        with tm.assert_produces_warning(warn):
+            # alignment for frame vs series comparisons deprecated
+            result = ser == ser[1]
         expected = tm.box_expected([False, False], xbox)
         tm.assert_equal(result, expected)
 
diff --git a/pandas/tests/frame/test_arithmetic.py b/pandas/tests/frame/test_arithmetic.py
index b3aa5e403e795..d9ef19e174700 100644
--- a/pandas/tests/frame/test_arithmetic.py
+++ b/pandas/tests/frame/test_arithmetic.py
@@ -795,13 +795,17 @@ def test_frame_with_zero_len_series_corner_cases():
     expected = pd.DataFrame(df.values * np.nan, columns=df.columns)
     tm.assert_frame_equal(result, expected)
 
-    result = df == ser
+    with tm.assert_produces_warning(FutureWarning):
+        # Automatic alignment for comparisons deprecated
+        result = df == ser
     expected = pd.DataFrame(False, index=df.index, columns=df.columns)
     tm.assert_frame_equal(result, expected)
 
     # non-float case should not raise on comparison
     df2 = pd.DataFrame(df.values.view("M8[ns]"), columns=df.columns)
-    result = df2 == ser
+    with tm.assert_produces_warning(FutureWarning):
+        # Automatic alignment for comparisons deprecated
+        result = df2 == ser
     expected = pd.DataFrame(False, index=df.index, columns=df.columns)
     tm.assert_frame_equal(result, expected)