diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 54cf8e12cfcf8..30c7abfee26a3 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -2426,22 +2426,25 @@ def _axes_are_unique(self) -> bool:
 
     def __getitem__(self, key):
 
-        if self.ndim == 2 and not self._axes_are_unique:
+        if self.ndim == 2:
             # GH#33041 fall back to .loc
             if not isinstance(key, tuple) or not all(is_scalar(x) for x in key):
                 raise ValueError("Invalid call for scalar access (getting)!")
-            return self.obj.loc[key]
+
+            if not self._axes_are_unique:
+                return self.obj.loc[key]
 
         return super().__getitem__(key)
 
     def __setitem__(self, key, value):
-        if self.ndim == 2 and not self._axes_are_unique:
+        if self.ndim == 2:
             # GH#33041 fall back to .loc
             if not isinstance(key, tuple) or not all(is_scalar(x) for x in key):
                 raise ValueError("Invalid call for scalar access (setting)!")
 
-            self.obj.loc[key] = value
-            return
+            if not self._axes_are_unique:
+                self.obj.loc[key] = value
+                return
 
         return super().__setitem__(key, value)
 
diff --git a/pandas/tests/indexing/test_at.py b/pandas/tests/indexing/test_at.py
index f6d2fb12c5d81..8ae4b4ea0b894 100644
--- a/pandas/tests/indexing/test_at.py
+++ b/pandas/tests/indexing/test_at.py
@@ -234,3 +234,11 @@ def test_at_categorical_integers(self):
             for key in [0, 1]:
                 with pytest.raises(KeyError, match=str(key)):
                     df.at[key, key]
+
+    def test_at_with_two_values(self):
+        # GH#48224
+        df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6]})
+
+        msg = "Invalid call for scalar access"
+        with pytest.raises(ValueError, match=msg):
+            df.at[slice(0, 1, None), "c"] = 7