Coach Ron Rivera said Williams suffered a foot injury in Sunday's 38-10 loss at Baltimore.
The Panthers (2-2) already were without Jonathan Stewart (who did not play on Sunday after suffering a sprained knee against Pittsburgh in Week 3), Mike Tolbert (short-term injured reserve, fractured leg) and Fozzy Whittaker (quad).
Williams, Stewart and Tolbert represent 12.61 percent ($13.9 million) of Carolina's salary cap.
Without them, Darrin Reaves and Chris Ogbonnaya are among the five active backs on the roster. Reaves and Tauren Poole were signed from the practice squad on consecutive Saturdays as emergency backs, but Poole was released after the Browns signed Ogbonnaya on Monday.
Ogbonnaya rushed 49 times for 240 yards and caught 48 passes for 343 yards and two touchdowns for the Browns last season.
"That's concerning," Rivera said of the running back situation. "And then you throw in the Mike Tolbert situation for us, you can say you've got six and only two are available. That's even more scary."
Rivera said before the Ogbonnaya signing that Reaves would begin the week as the starter.
"By default, if anything," Rivera said. "Believe me, it's not too big for him. That's the nice thing."
Rivera said Whittaker is on track to return to practice on Wednesday. The second-year player out of Texas led the team in rushing during the preseason, but he doesn't have a carry during the regular season.
Like Reaves and Poole, Whittaker was an undrafted player. The Panthers signed the former Texas standout during training camp because they lost sixth-round draft pick Tyler Gaffney for the year with a knee injury.
Williams injured his foot early in the second quarter on Sunday when trying to turn the corner on Ravens cornerback Jimmy Smith. Rivera said there was no structural damage.
Williams was making his first start after missing the previous two games with a hamstring injury.
Despite playing less than six quarters, Williams leads Carolina in rushing with 106 yards on 25 carries. Reaves has 12 carries for 26 yards and Poole one carry for no yards and a fumble.
The Panthers' running game that topped 100 yards in 14 of 16 games last season has failed to reach that mark in three consecutive games. It ranks 29th in the NFL with an average of 71 yards a game.
It wasn't all bad news. Rivera said quarterback Cam Newton, who missed the season opener with a fractured rib and spent much of the offseason recovering from left ankle surgery, is getting healthier to the point that the Panthers can "start to expand" the offense.
Newton accounted for 31.1 percent of the team's rush offense the past three seasons. He has rushed eight times for 33 yards the past three games, accounting for 11.6 percent of this year's rushing total.
Rivera said if the Panthers don't correct issues with the running game offensively and defensively -- Carolina ranks 27th against the run -- "it could be a long season for us."