Despite Mahomes proving to be the difference late, he was bottled up early by a sharp Titans defense, holding the Chiefs to just nine points in the first three quarters.
On the back of their strong defense, the Titans built a 14-9 lead at half-time as superstar running back Derrick Henry bulled his way into the endzone for two touchdowns.
Mahomes completed a first-half touchdown pass to Mecole Hardman, but a third-quarter field goal from the Titans had them trailing 17-9 heading into the fourth period.
With the game on the line, needing a touchdown and a two-point conversion to tie, Mahomes manufactured a 13-play, 93-yard drive, culminating in a 14-yard rushing touchdown from the Chiefs quarterback to convert on third-and-nine. He then also ran in the two-point conversion.
Mahomes completed passes to four different players in his one overtime drive, highlighted by a 27-yard jump-ball to Noah Gray to convert a third-and-inches and move into the redzone, before also converting a fourth-and-one to JuJu Smith-Schuster.
Ultimately they settled for a field goal, forcing Titans rookie quarterback Malik Willis to at least mount his own field-goal drive to keep the game alive, but the Chiefs defense rose to the occasion for the game-winning stop.
Mahomes ended up completing 43 of his 68 pass attempts for 446 yards, one touchdown and one interception, while also leading the Chiefs in rushing with six carries for 63 yards and a score to tie the game at 17-17.
That was in stark contrast to what the Titans asked Willis to do, as he finished five-of-16 for 80 yards. Henry was the star for Tennessee, rushing 17 times for 115 yards and two touchdowns, giving him nine touchdowns from eight games this season.