Spiller, picked ninth overall in this year's NFL draft, reached the end zone on a 20-yard run and a 1-yard dive. He finished with 52 yards on 12 carries and added 33 yards on two receptions.
Edwards was 13-of-17 for 153 yards for the 2-1 Bills. His scoring toss went 12 yards to Roscoe Parrish, who had four catches for 56 yards.
Ryan Fitzpatrick also looked solid for Buffalo, going 6-of-9 for 77 yards, including a 20-yard TD to rookie David Nelson.
Cincinnati quarterback Carson Palmer completed 9-of-11 passes, including a 6-yard scoring strike to Chad Ochocinco and a 9-yard scoring pass to rookie tight end Jermaine Gresham.
Terrell Owens caught three passes for 35 yards and Cedric Benson rushed for 50 yards on eight carries for the 2-2 Bengals.
Bengals third-string quarterback Jordan Palmer was intercepted in the fourth quarter by Reggie Corner, who returned it 20 yards for a touchdown.