Manuel hasn't played since Oct. 3, when he went down with a sprained lateral collateral ligament in his right knee in a game against Cleveland.
Marrone told reporters the promising rookie now is not expected to return any sooner than Nov. 17, when the Bills will be at home against the New York Jets.
Buffalo's first-round draft pick had passed for 985 yards with five touchdowns and three interceptions in five games prior to the injury.
The Bills (2-4) have lost two straight games in his absence.
Thaddeus Lewis will likely continue to fill in at quarterback until Manuel's return.