diff --git a/doc/source/whatsnew/v1.4.0.rst b/doc/source/whatsnew/v1.4.0.rst
index c3cf64c84510e..eb3fcfd74819d 100644
--- a/doc/source/whatsnew/v1.4.0.rst
+++ b/doc/source/whatsnew/v1.4.0.rst
@@ -697,6 +697,7 @@ Indexing
 - Bug in :meth:`DataFrame.loc.__getitem__` incorrectly raising ``KeyError`` when selecting a single column with a boolean key (:issue:`44322`).
 - Bug in setting :meth:`DataFrame.iloc` with a single ``ExtensionDtype`` column and setting 2D values e.g. ``df.iloc[:] = df.values`` incorrectly raising (:issue:`44514`)
 - Bug in indexing on columns with ``loc`` or ``iloc`` using a slice with a negative step with ``ExtensionDtype`` columns incorrectly raising (:issue:`44551`)
+- Bug in :meth:`DataFrame.loc.__setitem__` changing dtype when indexer was completely ``False`` (:issue:`37550`)
 - Bug in :meth:`IntervalIndex.get_indexer_non_unique` returning boolean mask instead of array of integers for a non unique and non monotonic index (:issue:`44084`)
 - Bug in :meth:`IntervalIndex.get_indexer_non_unique` not handling targets of ``dtype`` 'object' with NaNs correctly (:issue:`44482`)
 -
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index fc2204724aceb..f043a8cee308c 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -2058,6 +2058,8 @@ def ravel(i):
             # we have a frame, with multiple indexers on both axes; and a
             # series, so need to broadcast (see GH5206)
             if sum_aligners == self.ndim and all(is_sequence(_) for _ in indexer):
+                if is_empty_indexer(indexer[0], ser._values):
+                    return ser._values.copy()
                 ser = ser.reindex(obj.axes[0][indexer[0]], copy=True)._values
 
                 # single indexer
diff --git a/pandas/tests/frame/indexing/test_setitem.py b/pandas/tests/frame/indexing/test_setitem.py
index d30b726966e3d..9868cec633dff 100644
--- a/pandas/tests/frame/indexing/test_setitem.py
+++ b/pandas/tests/frame/indexing/test_setitem.py
@@ -922,6 +922,33 @@ def test_setitem_boolean_mask(self, mask_type, float_frame):
         expected.values[np.array(mask)] = np.nan
         tm.assert_frame_equal(result, expected)
 
+    @pytest.mark.xfail(reason="Currently empty indexers are treated as all False")
+    @pytest.mark.parametrize("box", [list, np.array, Series])
+    def test_setitem_loc_empty_indexer_raises_with_non_empty_value(self, box):
+        # GH#37672
+        df = DataFrame({"a": ["a"], "b": [1], "c": [1]})
+        if box == Series:
+            indexer = box([], dtype="object")
+        else:
+            indexer = box([])
+        msg = "Must have equal len keys and value when setting with an iterable"
+        with pytest.raises(ValueError, match=msg):
+            df.loc[indexer, ["b"]] = [1]
+
+    @pytest.mark.parametrize("box", [list, np.array, Series])
+    def test_setitem_loc_only_false_indexer_dtype_changed(self, box):
+        # GH#37550
+        # Dtype is only changed when value to set is a Series and indexer is
+        # empty/bool all False
+        df = DataFrame({"a": ["a"], "b": [1], "c": [1]})
+        indexer = box([False])
+        df.loc[indexer, ["b"]] = 10 - df["c"]
+        expected = DataFrame({"a": ["a"], "b": [1], "c": [1]})
+        tm.assert_frame_equal(df, expected)
+
+        df.loc[indexer, ["b"]] = 9
+        tm.assert_frame_equal(df, expected)
+
     @pytest.mark.parametrize("indexer", [tm.setitem, tm.loc])
     def test_setitem_boolean_mask_aligning(self, indexer):
         # GH#39931