Mahomes, the competition's reigning MVP, went off early in the second quarter with a knee injury, with his side leading 10-6.
But with back-up quarterback Matt Moore in fine form, the Chiefs came away to win 30-6, bolstering their win-loss record to 5-2 after surprise back-to-back losses to the Indianapolis Colts and the Houston Texans.
Mahomes had already completed 10 of 11 passes to gain 76 yards before he was injured in a pile-up near the Broncos' line. Medical personnel appeared to pop Mahomes' right knee back into place before he was helped from the field.
— Kansas City Chiefs (@Chiefs) October 18, 2019
The Chiefs turned in a dominant display against Denver, whose quarterback Joe Flacco was sacked a career-high eight times, with the home team held to just one-out-of-13 on third downs.
The Broncos were first on the scoreboard, earning their entire match points tally when Royce Freeman scored a touchdown from one yard after six minutes.
Mecole Hardman levelled the scores five minutes later after a 21-yard pass from Mahomes, the extra point and a subsequent field goal to Harrison Butker making it 10-6 at quarter time.
Another field goal to Butker and a touchdown off a five-yard fumble return by Reggie Ragland helped Kansas City to a 20-6 half time lead.
It became 27-6 with four minutes left in the third quarter when Tyreek Hill caught a 57-yard pass from Moore for a touchdown, before Butker added the only score of the last quarter with another field goal.
"Excited for the win," Moore said after completing 10 of 19 passes for 117 yards. "At the same time, a guy like Patrick goes down it can be deflating."
Before his injury, Mahomes became the fastest player in NFL history to throw for 7,500 yards, in his 25th game.