Manuel, whom Buffalo selected with the No. 16 pick in the first-round this year, will undergo minor knee surgery and have his status re-evaluated prior to the start of the regular season.
In his first two preseason games, the rookie from Florida State had completed 27-33 passes for 199 yards, 2 TD's and zero INT's.
Kolb, after missing Buffalo's first preseason game with a freak knee injury, struggled in his return this week, completing 13-21 passes for 119 yards, 0 TD's and an INT.
Manuel's injury is a blow to a Bills team beginning a rebuilding process under first-year head coach Doug Marrone, but it may give Kolb a final chance to salvage a once promising career.