Chiefs quarterback Mahomes limped off the field midway through the fourth quarter of Sunday's victory in Cleveland, which leaves Kansas City on 13-1 and firmly on course to secure home-field advantage through the post-season.
Chiefs medical staff could be seen strapping Mahomes' right and left ankles following the incident, which occurred after the quarterback was heavily tackled.
Mahomes played no further part in the game, with backup quarterback Carson Wentz taking over.
Three-time Super Bowl champion Mahomes finished with 159 passing yards and no interceptions in the victory.
In other early games on Sunday, Lamar Jackson threw five touchdowns in a dazzling performance as the Baltimore Ravens outclassed the New York Giants 35-14.
Jackson finished with 290 passing yards after completing 21-of-25 passes to help Baltimore improve to 9-5 for the season. The Giants fell to 2-12 with the loss.
The Ravens are second in the AFC North behind leaders Pittsburgh, who face the Philadelphia Eagles later Sunday.
Elsewhere, the Houston Texans moved to the brink of clinching the AFC South after a 20-12 win over the Miami Dolphins at the NRG Stadium.
The victory improves Houston to 9-5 for the season, and they could seal the divisional title later Sunday if the Indianapolis Colts (6-7) lose their road game against the Denver Broncos.
In New Orleans, the Washington Commanders hung on for a nail-biting 20-19 victory over the Saints. The Saints looked poised to snatch a win or force overtime after Foster Moreau's last-gasp touchdown left New Orleans just one point behind at 20-19.
But a New Orleans bid for a two-point conversion failed, allowing Washington to sneak victory.
