diff --git a/doc/source/whatsnew/v1.0.5.rst b/doc/source/whatsnew/v1.0.5.rst
index 7dfac54279e6f..fdf08dd381050 100644
--- a/doc/source/whatsnew/v1.0.5.rst
+++ b/doc/source/whatsnew/v1.0.5.rst
@@ -24,6 +24,8 @@ Note this disables the ability to read Parquet files from directories on S3
 again (:issue:`26388`, :issue:`34632`), which was added in the 1.0.4 release,
 but is now targeted for pandas 1.1.0.
 
+- Fixed regression in :meth:`~DataFrame.replace` raising an ``AssertionError`` when replacing values in an extension dtype with values of a different dtype (:issue:`34530`)
+
 .. _whatsnew_105.bug_fixes:
 
 Bug fixes
diff --git a/pandas/core/internals/blocks.py b/pandas/core/internals/blocks.py
index 13b98279169fd..38c495e1dd0f3 100644
--- a/pandas/core/internals/blocks.py
+++ b/pandas/core/internals/blocks.py
@@ -745,7 +745,11 @@ def replace(
             if is_object_dtype(self):
                 raise
 
-            assert not self._can_hold_element(value), value
+            if not self.is_extension:
+                # TODO: https://github.com/pandas-dev/pandas/issues/32586
+                # Need an ExtensionArray._can_hold_element to indicate whether
+                # a scalar value can be placed in the array.
+                assert not self._can_hold_element(value), value
 
             # try again with a compatible block
             block = self.astype(object)
diff --git a/pandas/tests/series/methods/test_replace.py b/pandas/tests/series/methods/test_replace.py
index 330c682216f53..8f57cf3191d5d 100644
--- a/pandas/tests/series/methods/test_replace.py
+++ b/pandas/tests/series/methods/test_replace.py
@@ -402,3 +402,8 @@ def test_replace_only_one_dictlike_arg(self):
         msg = "Series.replace cannot use dict-value and non-None to_replace"
         with pytest.raises(ValueError, match=msg):
             ser.replace(to_replace, value)
+
+    def test_replace_extension_other(self):
+        # https://github.com/pandas-dev/pandas/issues/34530
+        ser = pd.Series(pd.array([1, 2, 3], dtype="Int64"))
+        ser.replace("", "")  # no exception