diff --git a/src/strands/agent/agent.py b/src/strands/agent/agent.py
index f378a886a..ecfb2eb59 100644
--- a/src/strands/agent/agent.py
+++ b/src/strands/agent/agent.py
@@ -962,6 +962,14 @@ async def _convert_prompt_to_messages(self, prompt: AgentInput) -> Messages:
                         # Treat as List[ContentBlock] input - convert to user message
                         # This allows invalid structures to be passed through to the model
                         messages = [{"role": "user", "content": cast(list[ContentBlock], prompt)}]
+
+                    # Check if all items are interrupt responses
+                    elif all("interruptResponse" in item for item in prompt):
+                        raise ValueError(
+                            "Received interrupt responses but agent is not in interrupt state. "
+                            "Ensure the agent instance is preserved between calls, or use session "
+                            "management to persist interrupt state across requests."
+                        )
         else:
             messages = []
         if messages is None:
diff --git a/tests/strands/agent/test_agent.py b/tests/strands/agent/test_agent.py
index 967a0dafb..b0633f597 100644
--- a/tests/strands/agent/test_agent.py
+++ b/tests/strands/agent/test_agent.py
@@ -1866,6 +1866,15 @@ def test_agent__call__resume_interrupt_invalid_id():
         agent([{"interruptResponse": {"interruptId": "invalid", "response": None}}])
 
 
+def test_agent__call__resume_interrupt_not_activated():
+    """Passing interrupt responses to an agent not in interrupt state should raise a clear error."""
+    agent = Agent()
+
+    exp_message = r"Received interrupt responses but agent is not in interrupt state"
+    with pytest.raises(ValueError, match=exp_message):
+        agent([{"interruptResponse": {"interruptId": "test-id", "response": "yes"}}])
+
+
 def test_agent_structured_output_interrupt(user):
     agent = Agent()
     agent._interrupt_state.activated = True