diff --git a/doc/source/whatsnew/v1.4.1.rst b/doc/source/whatsnew/v1.4.1.rst
index 10b605f6ef43e..1604d5d1950d7 100644
--- a/doc/source/whatsnew/v1.4.1.rst
+++ b/doc/source/whatsnew/v1.4.1.rst
@@ -17,9 +17,10 @@ Fixed regressions
 - Regression in :meth:`Series.mask` with ``inplace=True`` and ``PeriodDtype`` and an incompatible ``other`` coercing to a common dtype instead of raising (:issue:`45546`)
 - Regression in :func:`.assert_frame_equal` not respecting ``check_flags=False`` (:issue:`45554`)
 - Regression in :meth:`Series.fillna` with ``downcast=False`` incorrectly downcasting ``object`` dtype (:issue:`45603`)
+- Regression in :meth:`DataFrame.iat` setting values leading to not propagating correctly in subsequent lookups (:issue:`45684`)
 - Regression in :meth:`DataFrame.loc.__setitem__` losing :class:`Index` name if :class:`DataFrame` was empty before (:issue:`45621`)
 - Regression in :func:`join` with overlapping :class:`IntervalIndex` raising an ``InvalidIndexError`` (:issue:`45661`)
--
+
 
 .. ---------------------------------------------------------------------------
 
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index eb2f734165ee9..48649174ce646 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -3876,15 +3876,15 @@ def _set_value(
         try:
             if takeable:
                 series = self._ixs(col, axis=1)
-                series._set_value(index, value, takeable=True)
-                return
-
-            series = self._get_item_cache(col)
-            loc = self.index.get_loc(index)
+                loc = index
+            else:
+                series = self._get_item_cache(col)
+                loc = self.index.get_loc(index)
 
-            # series._set_value will do validation that may raise TypeError
+            # setitem_inplace will do validation that may raise TypeError
             #  or ValueError
-            series._set_value(loc, value, takeable=True)
+            series._mgr.setitem_inplace(loc, value)
+
         except (KeyError, TypeError, ValueError):
             # set using a non-recursive method & reset the cache
             if takeable:
diff --git a/pandas/tests/indexing/test_iat.py b/pandas/tests/indexing/test_iat.py
index f1fe464ca0854..44bd51ee1b7d1 100644
--- a/pandas/tests/indexing/test_iat.py
+++ b/pandas/tests/indexing/test_iat.py
@@ -29,3 +29,20 @@ def test_iat_getitem_series_with_period_index():
     expected = ser[index[0]]
     result = ser.iat[0]
     assert expected == result
+
+
+def test_iat_setitem_item_cache_cleared(indexer_ial):
+    # GH#45684
+    data = {"x": np.arange(8, dtype=np.int64), "y": np.int64(0)}
+    df = DataFrame(data).copy()
+    ser = df["y"]
+
+    # previously this iat setting would split the block and fail to clear
+    #  the item_cache.
+    indexer_ial(df)[7, 0] = 9999
+
+    indexer_ial(df)[7, 1] = 1234
+
+    assert df.iat[7, 1] == 1234
+    assert ser.iloc[-1] == 1234
+    assert df.iloc[-1, -1] == 1234