Locker threw a 34-yard touchdown pass to rookie Justin Hunter with 15 seconds left and the Titans rallied to beat San Diego 20-17 Sunday.
It was their first win over the Chargers for the franchise since 1992 when the team was in Houston and Titans coach Mike Munchak still was playing for the then-Oilers.
The Titans (2-1) had lost nine straight to San Diego in the skid before Locker connected with Hunter for the rookie's first catch in the NFL.
"Honestly, once I threw it and saw them both jump to go up for it, it was so much higher than the guy guarding him, I started celebrating," Locker said of his winning pass.
Locker ended the slide by completing seven passes to six different receivers for 94 yards on the game-winning drive.
The eighth overall draft pick in 2011 finished with 299 yards passing and also ran for 68 yards and another touchdown.
"That's a huge game for him and this football team again," Munchak said of Locker.
The Chargers' final play featured seven laterals and even a kick of the ball trying to keep it alive before the game ended.
San Diego (1-2) led most of the game despite being banged up with three starters out because of injuries, a fourth very limited and a fifth lost to an injured foot in the first half.
"We had every opportunity to win the football game with the guys who were playing, we just didn't get it done at the end," Chargers coach Mike McCoy said.
Titans receiver Kenny Britt, booed heavily when he dropped the first pass of the game, was on the sideline throughout the final drive and finished without a catch despite five passes thrown to him.
Tennessee overcame a missed field goal and 10 penalties for 110 yards in the first half.
The Titans were flagged only once in the second half. They also lost two timeouts when Munchak lost replay challenges in the second half.
Linebacker Donald Butler was announced as inactive before San Diego made a late change scratching Tourek Williams instead. Butler was very limited by an injured groin. Left guard Chad Rinehart hurt his foot in the first half and didn't return.
"Yes, the answer was a mistake on our part," McCoy said of the confusion over the scratches.
The Titans only sacked Philip Rivers twice.
Still, the Chargers looked ready to win their second straight road game when Ronnie Brown capped a 67-yard drive with a 1-yard TD run with 2:42 left in the third quarter for a 17-10 lead.
Rivers put San Diego up 7-0 with a 7-yard TD pass to Antonio Gates to cap the Chargers' opening drive.
But Tennessee blocked a 38-yard field goal attempt Nick Novak to end the first half, and the teams were tied at 10 at halftime.
Then Rivers tried too hard to plead his case with an official who flagged the quarterback for unsportsmanlike conduct, giving the Chargers first-and-goal at the Titans 30. Rivers said he didn't say anything out of line but that was no excuse for drawing a penalty.
"They did take a touchdown off the board there," Rivers said. "I haven't seen the replay to know if it was the right call or not. Obviously, that's why I was so upset. That was a big play in the game when a touchdown gets called back."
San Diego settled for a 44-yard field goal by Novak for a 10-3 lead late in the second quarter.
The Titans had their chances as well. Hunter nearly had his first NFL catch and TD in the second quarter except a defender got an arm in early.
The Titans wound up punting with punter Brett Kern bobbling the ball, setting up Novak's field goal. The Titans also settled for two field goals by Rob Bironas, who also missed a 43-yarder wide right.
Rivers had been 6-0 against Tennessee ... The Titans have yet to turn the ball over this season ... The Titans are 4-1 when Locker has a passer rating of 90 or higher. He finished with a rating of 96.6 ... The Titans have won three of their past four home openers ... San Diego left tackle King Dunlap also got hurt late, but McCoy said he hadn't heard about all the injuries yet.