Marcus Mariota's tiebreaking 53-yard touchdown strike to rookie Taywan Taylor with 5:29 left in the game, coupled with Wesley Woodyard's stop of quarterback Jacoby Brissett on fourth down with 2:19 remaining, gave Tennessee a 36-22 victory at Nissan Stadium.
Mariota, who missed the Titans' 16-10 defeat at Miami the previous week with a hamstring injury, completed 23 of 32 passes for 306 yards as the Titans (3-3) moved into a three-way tie with Houston and Jacksonville for first place in the AFC South.
Woodyard helped seal the victory by running Brissett out of bounds just shy of the first down on fourth-and-1 at the Tennessee 13. A replay review confirmed the ruling, and the Titans iced it with a 72-yard touchdown run from Derrick Henry with 47 seconds left. It was their first victory over Indianapolis since October 30, 2011.
Henry finished with 131 yards on 19 carries.
The Colts (2-4) took a 19-9 lead 70 seconds into the third quarter when John Simon returned an interception 26 yards for a touchdown.
Ryan Succop drew Tennessee within 19-15 on 48- and 23-yard field goals, giving him five for the night. The Titans finally found the end zone with 10:01 left in the game on a 3-yard run by DeMarco Murray, capping a 15-play, 87-yard drive.
The Colts' Adam Vinatieri converted a 52-yard field goal with 7:27 left to even the score at 22, but all that did was tee up Tennessee's streak-breaking sequence.
Brissett hit on 21 of 37 passes for 212 yards and a touchdown.
Tennessee opened the scoring 3:45 into the game with Succop's 48-yard field goal. It was his 47th consecutive conversion from 50 yards or closer, an NFL record that he increased to 51 by game's end.
Indianapolis got a 36-yard field goal from Vinatieri to even the score, but Succop hit from 32 with 47 seconds left in the first quarter for a 6-3 lead.
The Colts took the lead with 10:54 left in the half as Brissett flipped an 8-yard touchdown pass to tight end Jack Doyle. The Titans responded with Succop's third field goal, a 40-yarder at the 4:10 mark, to slice their deficit to 10-9.
Indianapolis answered with a 25-yard field goal from Vinatieri 14 seconds before halftime, enabling the Colts to take a four-point lead to the locker room.
NOTES: Hedging its bets in terms of Marcus Mariota's return from a hamstring injury, Tennessee activated both backup quarterbacks -- Matt Cassel and Brandon Weeden. ... Indianapolis inserted Le'Raven Clark at right guard in place of Jack Mewhort, who was placed on injured reserve Saturday with a season-ending knee ailment. ... Titans NT Sylvester Williams was inactive after playing in the first five games and starting three. Austin Johnson got the start in his place.