diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 91f5cd1679a61..694ff60166d43 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -107,6 +107,7 @@
     is_list_like,
     is_scalar,
     is_sequence,
+    is_string_dtype,
     needs_i8_conversion,
     pandas_dtype,
 )
@@ -4454,8 +4455,12 @@ def _set_item_frame_value(self, key, value: DataFrame) -> None:
                 cols_droplevel = maybe_droplevels(cols, key)
                 if (
                     not isinstance(cols_droplevel, MultiIndex)
+                    and is_string_dtype(cols_droplevel.dtype)
                     and not cols_droplevel.any()
                 ):
+                    # if cols_droplevel contains only empty strings,
+                    # value.reindex(cols_droplevel, axis=1) would be full of NaNs
+                    # see GH#62518 and GH#61841
                     return
                 if len(cols_droplevel) and not cols_droplevel.equals(value.columns):
                     value = value.reindex(cols_droplevel, axis=1)
diff --git a/pandas/tests/indexing/multiindex/test_multiindex.py b/pandas/tests/indexing/multiindex/test_multiindex.py
index 2fe8f9affba2d..35ef7625b6e76 100644
--- a/pandas/tests/indexing/multiindex/test_multiindex.py
+++ b/pandas/tests/indexing/multiindex/test_multiindex.py
@@ -271,3 +271,24 @@ def test_multiindex_assign_aligns_as_implicit_tuple(self):
         df1["C"] = s1
         tm.assert_frame_equal(df1, df2)
         tm.assert_frame_equal(df1, df3)
+
+    def test_multiindex_assign_alignment_with_non_string_dtype(self):
+        # GH 62518
+        columns = MultiIndex.from_arrays(
+            [["a", "a", "z", "z"], pd.Categorical([1, 2, 1, 2])]
+        )
+
+        meta = DataFrame(columns=columns, dtype=object)
+        meta["z"] = meta["z"].astype("int64")
+
+        result = DataFrame(
+            data={
+                ("a", 1): Series([], dtype=object),
+                ("a", 2): Series([], dtype=object),
+                ("z", 1): Series([], dtype="int64"),
+                ("z", 2): Series([], dtype="int64"),
+            },
+            columns=columns,
+        )
+
+        tm.assert_frame_equal(meta, result)