diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 0f669beaa036f..ad84058d2b75a 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -446,6 +446,7 @@ Indexing
 
 Missing
 ^^^^^^^
+- Bug in :meth:`DataFrame.interpolate` failing to fill across multiblock data when ``method`` is "pad", "ffill", "bfill", or "backfill" (:issue:`53898`)
 - Bug in :meth:`DataFrame.interpolate` ignoring ``inplace`` when :class:`DataFrame` is empty (:issue:`53199`)
 - Bug in :meth:`Series.interpolate` and :meth:`DataFrame.interpolate` failing to raise on invalid ``downcast`` keyword, which can be only ``None`` or "infer" (:issue:`53103`)
 - Bug in :meth:`Series.interpolate` and :meth:`DataFrame.interpolate` with complex dtype incorrectly failing to fill ``NaN`` entries (:issue:`53635`)
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 8f213a1b7a1e2..59d22126ef0f0 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -7980,22 +7980,18 @@ def interpolate(
             raise ValueError("downcast must be either None or 'infer'")
 
         inplace = validate_bool_kwarg(inplace, "inplace")
-
         axis = self._get_axis_number(axis)
 
-        fillna_methods = ["ffill", "bfill", "pad", "backfill"]
-        should_transpose = axis == 1 and method not in fillna_methods
-
-        obj = self.T if should_transpose else self
-
-        if obj.empty:
+        if self.empty:
             if inplace:
                 return None
             return self.copy()
 
         if not isinstance(method, str):
             raise ValueError("'method' should be a string, not None.")
-        elif method.lower() in fillna_methods:
+
+        fillna_methods = ["ffill", "bfill", "pad", "backfill"]
+        if method.lower() in fillna_methods:
             # GH#53581
             warnings.warn(
                 f"{type(self).__name__}.interpolate with method={method} is "
@@ -8004,17 +8000,26 @@ def interpolate(
                 FutureWarning,
                 stacklevel=find_stack_level(),
             )
-        elif np.any(obj.dtypes == object):
-            # GH#53631
-            if not (obj.ndim == 2 and np.all(obj.dtypes == object)):
-                # don't warn in cases that already raise
-                warnings.warn(
-                    f"{type(self).__name__}.interpolate with object dtype is "
-                    "deprecated and will raise in a future version. Call "
-                    "obj.infer_objects(copy=False) before interpolating instead.",
-                    FutureWarning,
-                    stacklevel=find_stack_level(),
-                )
+            obj, should_transpose = self, False
+        else:
+            obj, should_transpose = (self.T, True) if axis == 1 else (self, False)
+            if np.any(obj.dtypes == object):
+                # GH#53631
+                if not (obj.ndim == 2 and np.all(obj.dtypes == object)):
+                    # don't warn in cases that already raise
+                    warnings.warn(
+                        f"{type(self).__name__}.interpolate with object dtype is "
+                        "deprecated and will raise in a future version. Call "
+                        "obj.infer_objects(copy=False) before interpolating instead.",
+                        FutureWarning,
+                        stacklevel=find_stack_level(),
+                    )
+
+        if "fill_value" in kwargs:
+            raise ValueError(
+                "'fill_value' is not a valid keyword for "
+                f"{type(self).__name__}.interpolate"
+            )
 
         if isinstance(obj.index, MultiIndex) and method != "linear":
             raise ValueError(
@@ -8023,23 +8028,22 @@ def interpolate(
 
         limit_direction = missing.infer_limit_direction(limit_direction, method)
 
-        if obj.ndim == 2 and np.all(obj.dtypes == np.dtype("object")):
+        if obj.ndim == 2 and np.all(obj.dtypes == object):
             raise TypeError(
                 "Cannot interpolate with all object-dtype columns "
                 "in the DataFrame. Try setting at least one "
                 "column to a numeric dtype."
             )
 
-        if "fill_value" in kwargs:
-            raise ValueError(
-                "'fill_value' is not a valid keyword for "
-                f"{type(self).__name__}.interpolate"
-            )
-
         if method.lower() in fillna_methods:
             # TODO(3.0): remove this case
             # TODO: warn/raise on limit_direction or kwargs which are ignored?
             #  as of 2023-06-26 no tests get here with either
+            if not self._mgr.is_single_block and axis == 1:
+                # GH#53898
+                if inplace:
+                    raise NotImplementedError()
+                obj, axis, should_transpose = self.T, 1 - axis, True
 
             new_data = obj._mgr.pad_or_backfill(
                 method=method,
diff --git a/pandas/tests/frame/methods/test_interpolate.py b/pandas/tests/frame/methods/test_interpolate.py
index ac862e5673411..fcdf7db35446e 100644
--- a/pandas/tests/frame/methods/test_interpolate.py
+++ b/pandas/tests/frame/methods/test_interpolate.py
@@ -451,8 +451,11 @@ def test_interp_string_axis(self, axis_name, axis_number):
         expected = df.interpolate(method="linear", axis=axis_number)
         tm.assert_frame_equal(result, expected)
 
+    @pytest.mark.parametrize("multiblock", [True, False])
     @pytest.mark.parametrize("method", ["ffill", "bfill", "pad"])
-    def test_interp_fillna_methods(self, request, axis, method, using_array_manager):
+    def test_interp_fillna_methods(
+        self, request, axis, multiblock, method, using_array_manager
+    ):
         # GH 12918
         if using_array_manager and axis in (1, "columns"):
             # TODO(ArrayManager) support axis=1
@@ -465,6 +468,10 @@ def test_interp_fillna_methods(self, request, axis, method, using_array_manager)
                 "C": [3.0, 6.0, 9.0, np.nan, np.nan, 30.0],
             }
         )
+        if multiblock:
+            df["D"] = np.nan
+            df["E"] = 1.0
+
         method2 = method if method != "pad" else "ffill"
         expected = getattr(df, method2)(axis=axis)
         msg = f"DataFrame.interpolate with method={method} is deprecated"