Jackson appeared to injure his calf during last Sunday's game against Miami and initial x-rays were negative, but head coach Chan Gailey said Wednesday the league's third-leading rusher will not play when the Bills visit East Rutherford on Sunday.
"Fred's not good, and I know he'll miss this one," Gailey said Wednesday. "Then we'll have to decide what happens from there."
There is speculation that Jackson could miss the remainder of the season.
Jackson entered last week's game against the Dolphins as the NFL's leading rusher, but was held to a just 17 yards on seven carries in the 35-8 loss as the Bills were forced to abandon the run after quickly falling behind.
With 934 yards rushing and 442 receiving yards, Jackson's combined total of 1,376 yards from scrimmage trails only Chicago's Matt Forte, who leads the league with 1,391 scrimmage yards.
C.J. Spiller will get the bulk of the workload at running back for the Bills, who have lost three in a row and take a 5-5 record into Sunday's matchup with the 5-5 Jets.