diff --git a/tests/v1/e2e/test_mamba_prefix_cache.py b/tests/v1/e2e/test_mamba_prefix_cache.py
index 7fe95366b9d5..6796294839bd 100644
--- a/tests/v1/e2e/test_mamba_prefix_cache.py
+++ b/tests/v1/e2e/test_mamba_prefix_cache.py
@@ -103,6 +103,7 @@ def fake_propose_draft_token_ids_fn(
         aux_hidden_states: list[torch.Tensor] | None,
         spec_decode_metadata: SpecDecodeMetadata | None,
         common_attn_metadata: CommonAttentionMetadata,
+        slot_mappings: dict[str, torch.Tensor] | list[dict[str, torch.Tensor]] | None,
     ) -> list[list[int]]:
         num_computed_tokens_cpu_tensor = self.input_batch.num_computed_tokens_cpu_tensor
         num_computed_tokens = num_computed_tokens_cpu_tensor[0].item()
@@ -473,10 +474,6 @@ def apply_patch(monkeypatch: pytest.MonkeyPatch):
     monkeypatch.setattr(mamba_utils, "do_mamba_copy_block", fake_copy_fn)
 
 
-@pytest.mark.skip(
-    reason="Skipping test_mamba_prefix_cache because it is based on spec "
-    "decode which is not allowed now."
-)
 def test_mamba_prefix_cache(monkeypatch: pytest.MonkeyPatch):
     run_ref_mamba_state_in_subprocess()
     apply_patch(monkeypatch)
diff --git a/vllm/model_executor/models/config.py b/vllm/model_executor/models/config.py
index cd462678b051..efd594c9e3d0 100644
--- a/vllm/model_executor/models/config.py
+++ b/vllm/model_executor/models/config.py
@@ -354,10 +354,6 @@ def verify_and_update_config(cls, vllm_config: "VllmConfig") -> None:
                 assert vllm_config.scheduler_config.enable_chunked_prefill, (
                     "Chunked prefill is required for mamba cache mode 'align'."
                 )
-                assert not vllm_config.speculative_config, (
-                    "Mamba cache mode 'align' is currently not compatible "
-                    "with speculative decoding."
-                )
             logger.info(
                 "Warning: Prefix caching in Mamba cache '%s' "
                 "mode is currently enabled. "
diff --git a/vllm/v1/core/sched/scheduler.py b/vllm/v1/core/sched/scheduler.py
index 20e9fced733c..5f745e39a16a 100644
--- a/vllm/v1/core/sched/scheduler.py
+++ b/vllm/v1/core/sched/scheduler.py
@@ -30,6 +30,7 @@
     RoutedExpertsReader,
 )
 from vllm.multimodal import MULTIMODAL_REGISTRY, MultiModalRegistry
+from vllm.utils.math_utils import round_down
 from vllm.v1.core.encoder_cache_manager import (
     EncoderCacheManager,
     EncoderDecoderCacheManager,
@@ -261,6 +262,14 @@ def has_mamba_layers(kv_cache_config: KVCacheConfig) -> bool:
                 vllm_config=self.vllm_config,
             )
 
+    def _mamba_compute_cache_pos(self, num_tokens_to_cache: int) -> int:
+        block_size = self.cache_config.block_size
+        last_cache_position = num_tokens_to_cache - num_tokens_to_cache % block_size
+        # eagle prune
+        if self.use_eagle:
+            last_cache_position = max(last_cache_position - block_size, 0)
+        return last_cache_position
+
     def _mamba_block_aligned_split(
         self,
         request: Request,
@@ -271,31 +280,44 @@ def _mamba_block_aligned_split(
         assert num_external_computed_tokens == 0, (
             "External KV connector is not verified yet"
         )
-        # TODO: need check for resume requests
-        if request.num_output_tokens == 0:  # prefill
+        num_computed_tokens = (
+            request.num_computed_tokens
+            + num_new_local_computed_tokens
+            + num_external_computed_tokens
+        )
+        # Perform block-aligned splitting at prefill phase, including:
+        # * non-resumed requests: num_computed_tokens < num_prompt_tokens + 0
+        # * resumed requests: num_computed_tokens < (
+        #                       num_prompt_tokens + num_output_tokens
+        #                     )
+        if num_computed_tokens < request.num_tokens:
             # To enable block-aligned caching of the Mamba state, `num_new_tokens`
             # must be a multiple of `block_size`.
             # As an exception, if `num_new_tokens` is less than `block_size`, the
             # state is simply not cached, requiring no special handling.
             # Additionally, when Eagle mode is enabled, FullAttn prunes the last
             # matching block. To prevent this from causing a Mamba cache miss, the
-            # last chunk must be larger than `block_size`.
-            block_size = self.cache_config.block_size
-            last_cache_position = (
-                request.num_prompt_tokens - request.num_prompt_tokens % block_size
-            )
-            # eagle prune
-            if self.use_eagle:
-                last_cache_position = max(last_cache_position - block_size, 0)
-            num_computed_tokens = (
-                request.num_computed_tokens
-                + num_new_local_computed_tokens
-                + num_external_computed_tokens
-            )
+            # last chunk must be not smaller than `block_size`.
+            num_tokens_to_cache = request.num_tokens
+            if request.num_output_tokens > 0:  # resumed requests
+                # Perform separate block-aligned splits for prompt and output tokens
+                # in resumed requests to maximize cache hits.
+                last_prompt_cache_position = self._mamba_compute_cache_pos(
+                    request.num_prompt_tokens
+                )
+                if num_computed_tokens < last_prompt_cache_position:
+                    num_new_tokens = min(
+                        num_new_tokens, request.num_prompt_tokens - num_computed_tokens
+                    )
+                    num_tokens_to_cache = request.num_prompt_tokens
+
+            last_cache_position = self._mamba_compute_cache_pos(num_tokens_to_cache)
             num_computed_tokens_after_sched = num_computed_tokens + num_new_tokens
             if num_computed_tokens_after_sched < last_cache_position:
                 # align to block_size
-                num_new_tokens = num_new_tokens // block_size * block_size
+                num_new_tokens = round_down(
+                    num_new_tokens, self.cache_config.block_size
+                )
             elif (
                 num_computed_tokens
                 < last_cache_position