Manuel will undergo a "minor knee procedure," the Bills said.
"He will miss the remainder of the preseason and then be re-evaluated at that time," coach Doug Marrone said in a statement.
Manuel played the entire third quarter of Friday's win over the Minnesota Vikings, completing 10-of-12 passes for 92 yards and a touchdown. The team did not announce any injury to Manuel during the game.
Through two games this preseason, Manuel completed 26 of 33 passes for 199 yards and two touchdowns, and ran four times for 29 yards.
Kolb was 13 of 21 for 111 yards and an interception on Sunday. Washington State rookie Jeff Tuel is the third-string quarterback.
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.
Marrone also announced that wide receiver Kevin Elliott "has a torn ACL and will miss the remainder of the season."
Information from The Associated Press was used in this report.