Fred Jackson, who took over the role in late November and finished with 1,062 yards, suffered a hand injury on the first possession of Friday night's preseason opener against the Washington Redskins at FedEx Field.
"We hope to be able to get him back for the first game," Bills coach Chan Gailey told reporters after the game. "Not sure."
Later on the opening drive, Lynch limped off the field with an ankle injury, leaving rookie C.J. Spiller atop the depth chart.
Spiller might sound like an attractive alternative because he was the ninth overall draft choice, but he's a scatback and doesn't possess the bruising, physical traits Jackson and Lynch have.
"When we lost those two guys we lost an awful lot of stuff we were trying to do in this ball game," Gailey said. "Those of you who watch practice saw a lot of the two-tailback stuff, and we were trying to use that quite a bit tonight. That kind of went out the gate when those two guys went down."