diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 45b5c16415f9d..dd27fd9e128ae 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -28,7 +28,7 @@ enhancement2
 
 Other enhancements
 ^^^^^^^^^^^^^^^^^^
--
+- Improve error message when setting :class:`DataFrame` with wrong number of columns through :meth:`DataFrame.isetitem` (:issue:`51701`)
 -
 
 .. ---------------------------------------------------------------------------
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index dbbe2c0751f3a..bac835cd35d8e 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -3897,6 +3897,12 @@ def isetitem(self, loc, value) -> None:
             if is_scalar(loc):
                 loc = [loc]
 
+            if len(loc) != len(value.columns):
+                raise ValueError(
+                    f"Got {len(loc)} positions but value has {len(value.columns)} "
+                    f"columns."
+                )
+
             for i, idx in enumerate(loc):
                 arraylike = self._sanitize_column(value.iloc[:, i])
                 self._iset_item_mgr(idx, arraylike, inplace=False)
diff --git a/pandas/tests/frame/methods/test_isetitem.py b/pandas/tests/frame/methods/test_isetitem.py
index 59328aafefefb..e8064cbc44d5f 100644
--- a/pandas/tests/frame/methods/test_isetitem.py
+++ b/pandas/tests/frame/methods/test_isetitem.py
@@ -1,3 +1,5 @@
+import pytest
+
 from pandas import (
     DataFrame,
     Series,
@@ -35,3 +37,14 @@ def test_isetitem_ea_df_scalar_indexer(self):
             }
         )
         tm.assert_frame_equal(df, expected)
+
+    def test_isetitem_dimension_missmatch(self):
+        # GH#51701
+        df = DataFrame({"a": [1, 2], "b": [3, 4], "c": [5, 6]})
+        value = df.copy()
+        with pytest.raises(ValueError, match="Got 2 positions but value has 3 columns"):
+            df.isetitem([1, 2], value)
+
+        value = df.copy()
+        with pytest.raises(ValueError, match="Got 2 positions but value has 1 columns"):
+            df.isetitem([1, 2], value[["a"]])