Favre went down in the Vikings' first offensive series, hurting his shoulder on a hard hit from Arthur Moats during his first pass attempt -- an interception by Drayton Florence.
But Jackson entered and went 15-of-22 passing, surviving three pickoffs for the Vikings (5-7), who won for the third time in five games and took their second straight under interim Coach Leslie Frazier.
Adrian Peterson, listed as questionable before the game, ran for 107 yards and three touchdowns for Minnesota. Sidney Rice hauled down five passes for 105 yards and two scores for the Vikings.
Ryan Fitzpatrick gained 158 yards and tossed a TD pass to David Nelson while going 15-of-25 through the air for Buffalo (2-10).