Manning hit Smith on 3- and 25-yard scoring strikes and connected with Hakeem Nicks on a 54-yarder, helping the Giants run up a 27-3 lead.
Smith gained 134 yards on 11 receptions.
Lawrence Tynes booted field goals of 25 and 40 yards for the Giants (4-0).
Manning was 20-of-24 passing for 292 yards.
Matt Cassel tossed fourth-quarter scoring passes of 1 yard to Sean Ryan and 2 yards to Bobby Wade for the Chiefs (0-4).
Kansas City has lost 15 of its last 16 games.