diff --git a/doc/source/whatsnew/v2.0.0.rst b/doc/source/whatsnew/v2.0.0.rst
index b1387e9717079..d0e10af7c51a5 100644
--- a/doc/source/whatsnew/v2.0.0.rst
+++ b/doc/source/whatsnew/v2.0.0.rst
@@ -876,6 +876,7 @@ Indexing
 - Bug in :meth:`DataFrame.iloc` raising ``IndexError`` when indexer is a :class:`Series` with numeric extension array dtype (:issue:`49521`)
 - Bug in :func:`~DataFrame.describe` when formatting percentiles in the resulting index showed more decimals than needed (:issue:`46362`)
 - Bug in :meth:`DataFrame.compare` does not recognize differences when comparing ``NA`` with value in nullable dtypes (:issue:`48939`)
+- Bug in :meth:`DataFrame.isetitem` coercing extension array dtypes in :class:`DataFrame` to object (:issue:`49922`)
 -
 
 Missing
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index e671f45216968..9365dc7761f2c 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -3822,6 +3822,15 @@ def isetitem(self, loc, value) -> None:
         In cases where `frame.columns` is unique, this is equivalent to
         `frame[frame.columns[i]] = value`.
         """
+        if isinstance(value, DataFrame):
+            if is_scalar(loc):
+                loc = [loc]
+
+            for i, idx in enumerate(loc):
+                arraylike = self._sanitize_column(value.iloc[:, i])
+                self._iset_item_mgr(idx, arraylike, inplace=False)
+            return
+
         arraylike = self._sanitize_column(value)
         self._iset_item_mgr(loc, arraylike, inplace=False)
 
diff --git a/pandas/tests/frame/methods/test_isetitem.py b/pandas/tests/frame/methods/test_isetitem.py
new file mode 100644
index 0000000000000..59328aafefefb
--- /dev/null
+++ b/pandas/tests/frame/methods/test_isetitem.py
@@ -0,0 +1,37 @@
+from pandas import (
+    DataFrame,
+    Series,
+)
+import pandas._testing as tm
+
+
+class TestDataFrameSetItem:
+    def test_isetitem_ea_df(self):
+        # GH#49922
+        df = DataFrame([[1, 2, 3], [4, 5, 6]])
+        rhs = DataFrame([[11, 12], [13, 14]], dtype="Int64")
+
+        df.isetitem([0, 1], rhs)
+        expected = DataFrame(
+            {
+                0: Series([11, 13], dtype="Int64"),
+                1: Series([12, 14], dtype="Int64"),
+                2: [3, 6],
+            }
+        )
+        tm.assert_frame_equal(df, expected)
+
+    def test_isetitem_ea_df_scalar_indexer(self):
+        # GH#49922
+        df = DataFrame([[1, 2, 3], [4, 5, 6]])
+        rhs = DataFrame([[11], [13]], dtype="Int64")
+
+        df.isetitem(2, rhs)
+        expected = DataFrame(
+            {
+                0: [1, 4],
+                1: [2, 5],
+                2: Series([11, 13], dtype="Int64"),
+            }
+        )
+        tm.assert_frame_equal(df, expected)