Manuel will undergo a "minor knee procedure" after an MRI revealed swelling in his left knee, the team announced.
It might be a "minor" procedure, but this is a major setback for the No. 16 pick in April's draft. Manuel had been in the driver's seat for the starting job after another solid preseason performance Friday night. He looked poised, comfortable and ready for the role.
Now, his status for the regular-season opener against the New England Patriots is in doubt. Even if Manuel is able to return in time for the regular season, his knee injury could be a lingering issue and, indeed, an ongoing storyline.
In Manuel's place, the Bills will turn to Kevin Kolb, who had a shaky debut Friday night as he played the entire first half. He will now have an opportunity to lead the Bills' offense.
Saturday's developments prove how quickly things can change in the NFL. One day after it appeared Manuel had all but locked up the starting job, Kolb has gotten his break in the competition.