It's unclear when or how Manuel was hurt. And there had been no indication the rookie first-round draft pick had been bothered by an injury following the game. He took over to start the second half and opened with a 14-play, 80-yard drive capped by a 4-yard touchdown pass to Brad Smith. He finished 10 of 12 for 92 yards in three series.
"E.J. Manuel had some swelling in his left knee this morning and was examined by our medical staff," Marrone said. "An MRI revealed that he will need to have a minor knee procedure and that has been scheduled. He will miss the remainder of the preseason and then be re-evaluated at that time."
The injury is a potentially significant setback for a player regarded the future of the franchise, and the only quarterback selected in the first round in April. He was chosen 16th overall out of Florida State.
Manuel is regarded as the center-piece of an offseason offensive overhaul under Marrone. The rookie head coach has been in the process of introducing an up-tempo offense with an emphasis on speed.
At 6-foot-4 and 240 pounds, Manuel is a strong-armed quarterback who has also has mobility.
The injury comes just as Manuel appeared to have taken the edge in an offseason-long quarterback competition with free-agent veteran addition Kevin Kolb.
Through two preseason games, Manuel completed 26 of 33 passes for 199 yards and two touchdowns, and ran four times for 29 yards.
Kolb had just returned to practice last week after missing eight days with a twisted left knee, which he hurt while slipping on a wet rubber mat during practice on Aug. 3.
In starting against Minnesota on Friday, Kolb got off to a slow start. He finished 13 of 21 for 111 yards passing and an interception. Washington State rookie Jeff Tuel is the third-string quarterback.
Kolb will now start against Washington next Saturday.
Kolb signed with the Bills in the offseason after starting 21 of 32 career games played in a six-year career with Philadelphia and Arizona. He's thrown for 28 touchdowns and 25 interceptions while being sacked 77 times in a career that started as a second-round draft pick of the Eagles in 2007.