diff --git a/doc/source/whatsnew/v1.3.0.rst b/doc/source/whatsnew/v1.3.0.rst
index 63902b53ea36d..8319aa957d232 100644
--- a/doc/source/whatsnew/v1.3.0.rst
+++ b/doc/source/whatsnew/v1.3.0.rst
@@ -620,6 +620,7 @@ Missing
 
 - Bug in :class:`Grouper` now correctly propagates ``dropna`` argument and :meth:`DataFrameGroupBy.transform` now correctly handles missing values for ``dropna=True`` (:issue:`35612`)
 - Bug in :func:`isna`, and :meth:`Series.isna`, :meth:`Index.isna`, :meth:`DataFrame.isna` (and the corresponding ``notna`` functions) not recognizing ``Decimal("NaN")`` objects (:issue:`39409`)
+- Bug in :meth:`Series.fillna` and :meth:`DataFrame.fillna` overwriting missing values in indices skipped by the ``value`` argument (:issue:`40498`)
 -
 
 MultiIndex
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 8524907a84099..affcc821457e8 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -6524,6 +6524,11 @@ def fillna(
                         value, dtype_if_empty=object
                     )
                     value = value.reindex(self.index, copy=False)
+
+                    # GH-40498: Indices to not apply fillna to are marked with NaN,
+                    # but that will still cause other missing values to be replaced
+                    # with NaN (which is problematic if those aren't NaN)
+                    value.loc[self.isna() & value.isna()] = self
                     value = value._values
                 elif not is_list_like(value):
                     pass
diff --git a/pandas/tests/frame/methods/test_fillna.py b/pandas/tests/frame/methods/test_fillna.py
index 564481d01abc8..253b34639faf2 100644
--- a/pandas/tests/frame/methods/test_fillna.py
+++ b/pandas/tests/frame/methods/test_fillna.py
@@ -153,6 +153,19 @@ def test_fillna_tzaware_different_column(self):
         )
         tm.assert_frame_equal(result, expected)
 
+    def test_other_missing_vals_not_modified(
+        self, unique_nulls_fixture, unique_nulls_fixture2
+    ):
+        # GH-40498
+        missing_val1, missing_val2 = unique_nulls_fixture, unique_nulls_fixture2
+        df = DataFrame(
+            {"A": [1, missing_val1, missing_val2], "B": [2, missing_val1, missing_val2]}
+        )
+        filler = {"A": {1: 0}, "B": {2: 0}}
+        result = df.fillna(filler)
+        expected = DataFrame({"A": [1, 0, missing_val2], "B": [2, missing_val1, 0]})
+        tm.assert_frame_equal(result, expected)
+
     def test_na_actions_categorical(self):
 
         cat = Categorical([1, 2, 3, np.nan], categories=[1, 2, 3])
diff --git a/pandas/tests/series/methods/test_fillna.py b/pandas/tests/series/methods/test_fillna.py
index cf6b357d0a418..d7b873ff14357 100644
--- a/pandas/tests/series/methods/test_fillna.py
+++ b/pandas/tests/series/methods/test_fillna.py
@@ -620,6 +620,16 @@ def test_fillna_numeric_inplace(self):
         expected = x.fillna(value=0)
         tm.assert_series_equal(y, expected)
 
+    def test_fillna_does_not_modify_other_missing_vals(
+        self, unique_nulls_fixture, unique_nulls_fixture2
+    ):
+        # GH-40498
+        missing_val1, missing_val2 = unique_nulls_fixture, unique_nulls_fixture2
+        ser = Series([1, missing_val1, missing_val2, ""])
+        result = ser.fillna({2: 0})
+        expected = Series([1, missing_val1, 0, ""])
+        tm.assert_series_equal(result, expected)
+
     # ---------------------------------------------------------------
     # CategoricalDtype