Mariota's 3-yard touchdown toss to Dorial Green-Beckham in the third quarter was his eighth this season, tying Mark Rypien's record set in 1988 with Washington. Mariota had six touchdown passes in the first two games. He connected with Kendall Wright on a 7-yard touchdown pass late in the second quarter.
Stil, Tennessee couldn't withstand a fierce fourth-quarter comeback by Indianapolis. The Colts scored 21 straight points, then stopped the Titans on a potential game-tying two-point conversion attempt to win 35-33.
For Mariota's first interception, he hit tight end Delanie Walker, only to have the pass go off the veteran's hands and straight to Colts safety Dwight Lowery, who returned it 69 yards for a touchdown.
That gave the winless Colts a 14-0 lead early in the second quarter against the Titans.
Then the Colts stalled. The Titans poured on 27 unanswered points to lead 27-14 at the end of the third quarter.
Colts quarterback Andrew Luck set a new low Sunday with eight pass attempts, the fewest of his career in any half. Luck had thrown 12 passes in a half twice before in his career, according to Stats LLC.
The Colts have now won eight straight and 13 of the past 14 in this series between AFC South rivals. Luck is 17-2 against the AFC South since entering the NFL in 2012 and tiedPeyton Manning for the most consecutive wins (14) in division games since realignment.
Mariota entered the game leading the NFL with a 129.9 passer rating. He threw a second interception in the fourth quarter that led to the Colts' go-ahead score.
"I thought I could fit it in there. The safety made a good play. I've got to be smarter," Mariota said. "Delanie was one-on-one underneath. Just take that and get the first down."
ESPN Titans reporter Paul Kuharsky and The Associated Press contributed to this report.
Mariota's first INT goes for a touchdown
Titans QB Marcus Mariota's pass intended for Delanie Walker gets picked off by Colts S Dwight Lowery, who returns the ball 69 yards for a touchdown.
Mariota being asked to do too much
Jim Basquil and Ron Jaworski break down the Colts' 35-33 win over the Titans.