Mariota produced one of the grittiest performances of his career on his return Monday after sustaining a hamstring injury.
Even with his mobility reduced, the quarterback was able to connect with Taywan Taylor to give the Titans the lead with just over five minutes remaining.
The Titans sealed the win with a 72-yard touchdown run by Derrick Henry with 47 seconds remaining, thus ending their 11-game losing streak to the Indianapolis Colts.
It is Tennessee's first victory over Indianapolis since October 2011.
Mariota managed to complete 23-of-32 passes for 306 yards with one touchdown and one interception.
The Colts led 13-9 at halftime and took a 19-9 lead 70 seconds into the third quarter when John Simon returned an interception 26 yards for a touchdown, but the Titans took control thereafter.
The Titans now move into a tie for first place in the AFC South.