MVP-favourite Mahomes suffered what appeared to be an ankle injury during the first quarter of Saturday's game, in a potentially huge blow to Kansas City.
The quarterback returned to the field with heavy strapping around his ankle, though it was clear he was struggling as he hobbled forward before throwing the ball to the ground, paving the way for Harrison Butker to kick a 50-yard field goal to edge the Chiefs into a three-point lead.
Mahomes seemed to be debating whether he could continue with head coach Andy Reid, before he eventually headed down to the locker room.
The 27-year-old did not look happy with the decision, as veteran back-up Chad Henne, a former Jaguars QB, came on in his place.
Henne's first task was to get the ball out of the Chiefs' own end zone, though he managed to do so as Mahomes returned to watch on from the sideline with his status uncertain.
Mahomes was able to watch his team extend their lead after Isiah Pacheco's brilliant drive set the stage for Henne to find Travis Kelce, who went over for his second touchdown of the game.