diff --git a/pandas/core/internals/managers.py b/pandas/core/internals/managers.py
index 2a404f46dcc47..7bb579b22aeed 100644
--- a/pandas/core/internals/managers.py
+++ b/pandas/core/internals/managers.py
@@ -370,8 +370,30 @@ def setitem(self, indexer, value) -> Self:
             raise ValueError(f"Cannot set values with ndim > {self.ndim}")
 
         if using_copy_on_write() and not self._has_no_reference(0):
-            # if being referenced -> perform Copy-on-Write and clear the reference
             # this method is only called if there is a single block -> hardcoded 0
+            # Split blocks to only copy the columns we want to modify
+            if self.ndim == 2 and isinstance(indexer, tuple):
+                blk_loc = self.blklocs[indexer[1]]
+                if is_list_like(blk_loc) and blk_loc.ndim == 2:
+                    blk_loc = np.squeeze(blk_loc, axis=0)
+                elif not is_list_like(blk_loc):
+                    # Keep dimension and copy data later
+                    blk_loc = [blk_loc]  # type: ignore[assignment]
+                if len(blk_loc) == 0:
+                    return self.copy(deep=False)
+
+                values = self.blocks[0].values
+                if values.ndim == 2:
+                    values = values[blk_loc]
+                    # "T" has no attribute "_iset_split_block"
+                    self._iset_split_block(  # type: ignore[attr-defined]
+                        0, blk_loc, values
+                    )
+                    # first block equals values
+                    self.blocks[0].setitem((indexer[0], np.arange(len(blk_loc))), value)
+                    return self
+            # No need to split if we either set all columns or on a single block
+            # manager
             self = self.copy()
 
         return self.apply("setitem", indexer=indexer, value=value)
diff --git a/pandas/tests/copy_view/test_indexing.py b/pandas/tests/copy_view/test_indexing.py
index c58aeecad22e3..ebb25bd5c57d3 100644
--- a/pandas/tests/copy_view/test_indexing.py
+++ b/pandas/tests/copy_view/test_indexing.py
@@ -1028,16 +1028,15 @@ def test_dataframe_add_column_from_series(backend, using_copy_on_write):
         (tm.iloc, (slice(None), 0)),
     ],
 )
+@pytest.mark.parametrize(
+    "col", [[0.1, 0.2, 0.3], [7, 8, 9]], ids=["mixed-block", "single-block"]
+)
 def test_set_value_copy_only_necessary_column(
-    using_copy_on_write,
-    indexer_func,
-    indexer,
-    val,
+    using_copy_on_write, indexer_func, indexer, val, col
 ):
     # When setting inplace, only copy column that is modified instead of the whole
     # block (by splitting the block)
-    # TODO multi-block only for now
-    df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6], "c": [0.1, 0.2, 0.3]})
+    df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6], "c": col})
     df_orig = df.copy()
     view = df[:]
 
diff --git a/pandas/tests/copy_view/test_methods.py b/pandas/tests/copy_view/test_methods.py
index fe869183e307a..fe1be2d8b6a0a 100644
--- a/pandas/tests/copy_view/test_methods.py
+++ b/pandas/tests/copy_view/test_methods.py
@@ -489,7 +489,8 @@ def test_shift_no_op(using_copy_on_write):
 
     df.iloc[0, 0] = 0
     if using_copy_on_write:
-        assert not np.shares_memory(get_array(df, "b"), get_array(df2, "b"))
+        assert not np.shares_memory(get_array(df, "a"), get_array(df2, "a"))
+        assert np.shares_memory(get_array(df, "b"), get_array(df2, "b"))
     tm.assert_frame_equal(df2, df_orig)
 
 
@@ -532,16 +533,16 @@ def test_shift_columns(using_copy_on_write):
     df2 = df.shift(periods=1, axis=1)
 
     assert np.shares_memory(get_array(df2, "2020-01-02"), get_array(df, "2020-01-01"))
-    df.iloc[0, 1] = 0
+    df.iloc[0, 0] = 0
     if using_copy_on_write:
         assert not np.shares_memory(
             get_array(df2, "2020-01-02"), get_array(df, "2020-01-01")
         )
-    expected = DataFrame(
-        [[np.nan, 1], [np.nan, 3], [np.nan, 5]],
-        columns=date_range("2020-01-01", "2020-01-02"),
-    )
-    tm.assert_frame_equal(df2, expected)
+        expected = DataFrame(
+            [[np.nan, 1], [np.nan, 3], [np.nan, 5]],
+            columns=date_range("2020-01-01", "2020-01-02"),
+        )
+        tm.assert_frame_equal(df2, expected)
 
 
 def test_pop(using_copy_on_write):
@@ -1335,13 +1336,18 @@ def test_droplevel(using_copy_on_write):
 
     if using_copy_on_write:
         assert np.shares_memory(get_array(df2, "c"), get_array(df, "c"))
+        assert np.shares_memory(get_array(df2, "a"), get_array(df, "a"))
     else:
         assert not np.shares_memory(get_array(df2, "c"), get_array(df, "c"))
+        assert not np.shares_memory(get_array(df2, "a"), get_array(df, "a"))
 
     # mutating df2 triggers a copy-on-write for that column / block
     df2.iloc[0, 0] = 0
 
-    assert not np.shares_memory(get_array(df2, "c"), get_array(df, "c"))
+    assert not np.shares_memory(get_array(df2, "a"), get_array(df, "a"))
+    if using_copy_on_write:
+        assert np.shares_memory(get_array(df2, "b"), get_array(df, "b"))
+
     tm.assert_frame_equal(df, df_orig)
 
 
diff --git a/pandas/tests/indexing/test_loc.py b/pandas/tests/indexing/test_loc.py
index b314c20568f64..abbf22a7fc70a 100644
--- a/pandas/tests/indexing/test_loc.py
+++ b/pandas/tests/indexing/test_loc.py
@@ -2646,6 +2646,13 @@ def test_loc_indexer_all_false_broadcast(self):
         df.loc[np.array([False], dtype=np.bool_), ["a"]] = df["b"]
         tm.assert_frame_equal(df, expected)
 
+    def test_loc_indexer_length_one(self):
+        # GH#51435
+        df = DataFrame({"a": ["x"], "b": ["y"]}, dtype=object)
+        expected = DataFrame({"a": ["y"], "b": ["y"]}, dtype=object)
+        df.loc[np.array([True], dtype=np.bool_), ["a"]] = df["b"]
+        tm.assert_frame_equal(df, expected)
+
 
 class TestLocListlike:
     @pytest.mark.parametrize("box", [lambda x: x, np.asarray, list])