Hoyer sustained a potentially serious right knee injury on a scramble in the first quarter, and Manuel was forced out after taking a helmet to his right knee on a run in the third. Neither returned and their injuries could impact both teams' seasons.
C.J. Spiller had a 54-yard TD run and Fred Jackson had a pair of 1-yard TD runs for the Bills, who could do nothing on offense once Manuel left the game.
Billy Cundiff kicked field goals of 24 and 44 yards in the fourth quarter for the Browns, who overcame a 10-0 deficit and were down 24-17 less than two minutes into the second quarter.
Cundiff's second kick with 2:01 left put the Browns ahead 30-24, and Cleveland turned it over to their third-ranked overall defense.
With the Bills still within a TD, Tuel locked in on Robert Woods and never saw Ward, who cut in front of the receiver and scored untouched, allowing Cleveland fans to relax following a hectic second half.
Travis Benjamin had an electrifying 79-yard TD punt return in the first half for Cleveland.
Beyond the quarterbacks, both teams had one other key player go down with an injury.
Bills leading receiver Stevie Johnson injured his back in the first half and didn't return. Johnson caught two catches for 19 yards before he went out.
Browns defensive end Desmond Bryant was taken to the Cleveland Clinic in the third quarter after experiencing shortness of breath. Last year with Oakland, Bryant had to be hospitalized during a game with an irregular heartbeat, but returned to play the next week.