He missed Sunday's game due to a shoulder injury and the team is preparing for a "multi-week absence."
The 2019 first-team All-Pro has struggled to stay healthy this season after an ankle injury in September cost him six weeks before he suffered the shoulder injury in his first game back against the Kansas City Chiefs.
It has already caused him to miss one game and appears likely to lead to more missed time.
It's certainly not the way either McCaffrey or the Panthers wanted his four-year, $64 million extension to begin, though there's little question he is worth the money when healthy. In three games this season, the tailback is averaging 3.8 yards per carry and 8.8 yards per catch with six total touchdowns.
Now first-year head coach Matt Rhule will have to tailor the offense to play without the 24-year-old once again, with the Panthers already stuck in last place in the NFC South at at 3-7.
Carolina is likely to rely on backups Mike Davis and Rodney Smith in the backfield for the time being, but not even a running-back-by-committee approach can make up for the loss of McCaffrey as both a rusher and route-runner.
The 2020 season hasn't been kind to the Panthers and it doesn't seem like it's getting better anytime soon, especially with its dynamic playmaker being unable to stay on the field.