The combination again proved unbeatable.
Luck threw for a season high 393 yards and four touchdowns, and Wayne had his first 100-yard game and first touchdown of the season as Indianapolis rolled past Tennessee 41-17.
"He (Wayne) got a game ball. I probably should have given him two," coach Chuck Pagano joked.
When Luck and Wayne first teamed up in 2012, the veteran receiver quickly embraced the rookie quarterback and it didn't take long for them to develop a rapport on the field and a friendship off of it. They became the key players in a remarkable turnaround that season, going from 2-14 to 10-6 and back to the playoffs. Last season, they were working well until Wayne sustained a season-ending torn ACL in October.
This year, some questioned whether the 25-year-old quarterback and 35-year-old receiver could get back in sync -- doubts that were erased against Tennessee.
Luck completed 29 of 41 passes with one interception, and Wayne had seven receptions for 119 yards including a spectacular, spinning 28-yard TD catch down the sideline that gave Indy control midway through the third quarter.
Luck has now thrown for 763 yards and eight touchdowns in the last two games.
Wayne turned his 200th career game into a showcase. He passed Isaac Bruce for seventh on the NFL's career receptions list, Henry Ellard for 10th in career yards receiving and extended his NFL record for consecutive games with three or more catches to 75. Wayne now has 1,029 catches, 13,873 yards and 81 TD receptions.
Those weren't the numbers Wayne cared about.
After starting this season with back-to-back losses, Indy (2-2) has now won twice by more than 20 points and has extended its league-high streak of consecutive wins over division opponents to nine.
"It was an opportunity for us to put our foot down in the division," Wayne said. "We let everybody know the Colts -- we're pretty solid."
Tennessee (1-3) never had a chance with starting quarterback Jake Locker out because of a right wrist injury.
Charlie Whitehurst, a nine-year veteran, made his fifth career start. Although he didn't play badly, he was yanked midway through the fourth quarter. Whitehurst finished 12 of 23 for 177 yards with one TD, the fourth of his career, and one interception. He also rushed five times for 40 yards.
The Titans didn't reach the end zone until Whitehurst threw a 7-yard TD pass to Delanie Walker with 13 seconds left in the half to make it 20-10. Tennessee didn't score again until Bishop Sankey's 2-yard run with 35 seconds left in the third quarter, but that only cut the deficit to 34-17.
What's wrong with a team that has followed an impressive season-opening win over Kansas City with three straight losses?
"I can't even put my finger on that," receiver Kendall Wright said. "... We have to put some wins up there and we have to stop all of the little things that's killing us."
Wright was responsible for one of those big miscues against Indy.
Two plays after the Colts recovered Wright's fumble, Trent Richardson scored on a 1-yard TD run. Pat McAfee followed that with a surprise onside kick that Indy recovered. Eleven plays later, Luck hooked up with Dwayne Allen for a 7-yard TD pass and a 14-0 lead.
Tennessee got back into the game after converting Luck's interception into Walker's TD catch, but it was short-lived.
Wayne's incredible catch and Luck's 2-yard TD pass to Coby Fleener with 4:02 left in the third gave Indy a 34-10 cushion.
"You want guys that can go out there and make plays," Luck said. "To be able to spread the ball out and get everybody involved, that's important -- and it worked today."
Indy receiver T.Y. Hilton had six receptions for 105 yards. .... Rookie Zach Mettenberger relieved Whitehurst and finished the game 2 of 5 for 17 yards with an interception. ... Walker finished with five catches for 84 yards to lead the Titans. ... Colts safety Mike Adams had two interceptions. ... Indy kept the ball for 42:21, compared with 17:39 for the Titans. ... Indy has scored 85 points in the last two games.
AP NFL websites: www.pro32.ap.org and www.twitter.com/AP-NFL