diff --git a/moto/ec2/exceptions.py b/moto/ec2/exceptions.py
index 6eb8d515e..780ed933c 100644
--- a/moto/ec2/exceptions.py
+++ b/moto/ec2/exceptions.py
@@ -444,6 +444,14 @@ class InvalidParameterValueErrorTagSpotFleetRequest(EC2ClientError):
         )
 
 
+class InvalidParameterValueErrorReplaceRoute(EC2ClientError):
+    def __init__(self, cidr: str):
+        super().__init__(
+            "InvalidParameterValue",
+            f"There is no route defined for '{cidr}' in the route table. Use CreateRoute instead.",
+        )
+
+
 class EmptyTagSpecError(EC2ClientError):
     def __init__(self) -> None:
         super().__init__(
diff --git a/moto/ec2/models/route_tables.py b/moto/ec2/models/route_tables.py
index de6217d09..51c8e2e76 100644
--- a/moto/ec2/models/route_tables.py
+++ b/moto/ec2/models/route_tables.py
@@ -18,6 +18,7 @@ from ..exceptions import (
     InvalidRouteTableIdError,
     InvalidAssociationIdError,
     InvalidDestinationCIDRBlockParameterError,
+    InvalidParameterValueErrorReplaceRoute,
     RouteAlreadyExistsError,
     RouteNotSupportedError,
 )
@@ -451,7 +452,18 @@ class RouteBackend:
         route_id = generate_route_id(
             route_table.id, destination_cidr_block, destination_ipv6_cidr_block
         )
-        route = route_table.routes[route_id]
+        try:
+            route = route_table.routes[route_id]
+        except KeyError:
+            cidr = (
+                destination_cidr_block
+                if destination_cidr_block
+                else destination_ipv6_cidr_block
+            )
+            # This should be 'raise InvalidRouteError(route_table_id, cidr)' in
+            # line with the delete_route() equivalent, but for some reason AWS
+            # returns InvalidParameterValue instead in this case.
+            raise InvalidParameterValueErrorReplaceRoute(cidr) from None
 
         route.gateway = None
         route.nat_gateway = None