diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 87ab0d94a7ce0..a9919f8f2e290 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -2106,7 +2106,9 @@ def _setitem_with_indexer_missing(self, indexer, value):
                     return self._setitem_with_indexer(new_indexer, value, "loc")
 
             # this preserves dtype of the value and of the object
-            if is_valid_na_for_dtype(value, self.obj.dtype):
+            if not is_scalar(value):
+                new_dtype = None
+            elif is_valid_na_for_dtype(value, self.obj.dtype):
                 value = na_value_for_dtype(self.obj.dtype, compat=False)
                 new_dtype = maybe_promote(self.obj.dtype, value)[0]
             elif isna(value):
diff --git a/pandas/tests/series/indexing/test_indexing.py b/pandas/tests/series/indexing/test_indexing.py
index 5e87e36f21cca..0bab391dab27d 100644
--- a/pandas/tests/series/indexing/test_indexing.py
+++ b/pandas/tests/series/indexing/test_indexing.py
@@ -358,6 +358,15 @@ def test_loc_boolean_indexer_miss_matching_index():
         ser.loc[indexer]
 
 
+def test_loc_setitem_nested_data_enlargement():
+    # GH#48614
+    df = DataFrame({"a": [1]})
+    ser = Series({"label": df})
+    ser.loc["new_label"] = df
+    expected = Series({"label": df, "new_label": df})
+    tm.assert_series_equal(ser, expected)
+
+
 class TestDeprecatedIndexers:
     @pytest.mark.parametrize("key", [{1}, {1: 1}])
     def test_getitem_dict_and_set_deprecated(self, key):