Panthers coach Matt Rhule told reporters on Saturday that Darnold's injury is "significant", and the former first-round pick will undergo further testing to determine a timetable for a return.
"We're not sure we have the exact length," Ruhle said. "We've sent images to specialists to try to gauge it. But again, that does look like a significant injury that could take some time."
Darnold was carted off during the third quarter of Carolina's 21-0 win after landing awkwardly when hit by Buffalo defensive tackle C.J. Brewer.
The fifth-year QB was slated to be the primary backup to offseason addition Baker Mayfield, whom Ruhle declared the starter earlier in the week.
Ruhle acknowledged Darnold could begin the season on short-term injured reserve, which would keep him out for at least four games.
With both Darnold and rookie Matt Corral out, P.J. Walker is expected to serve as the number two QB for the September 11 opener against Cleveland.
Corral, a third-round pick in this year's draft, sustained a season-ending Lisfranc injury in last week's game at New England.
"We have two quarterbacks [and] normally we would go into the season with two," Ruhle said. "Sam, I think he will be back. It's just a matter of how many weeks it is."
Ruhle also said kicker Zane Gonzalez will be sidelined indefinitely with a groin injury that also took place in the third quarter of Friday's game.
"He's going to be seen by a specialist, and that will lead to any future decisions that have to be made," Ruhle said. "But it is a significant injury to his groin.
"He's a warrior. He'll find a way to battle back, and we'll find out exactly what the length of that is."
Gonzalez is coming off a strong 2021 season in which he converted 20 of 22 field goal attempts and 22 of 23 point-after tries.