Fred Jackson missed the final six games last season with a broken leg. On Sunday, he suffered another leg injury that took him out of the game.
The running back exited the Buffalo Bills' season opener against the New York Jets after suffering a lower leg injury during the first half at MetLife Stadium.
CBSSports.com's Jason La Canfora reported the initial diagnosis is a sprained lateral collateral ligament in Jackson's knee.
C.J. Spiller replaced Jackson and busted a 56-yard touchdown run on his third carry. If Jackson is forced to miss extended time, Spiller could be in position to steal carries once Jackson returns.
"Both of them were knees," coach Chan Gailey told the Bills' official website. "Fred doesn't look as bad as David (Nelson). We don't know how bad David is, but it doesn't look good right now. Fred doesn't look nearly as bad, but we're going to get a further evaluation tomorrow."
Jackson later on Twitter thanked fans for their support.