Chris Hope intercepted Manning twice and the Titans defense stopped the Colts twice on fourth down during a 31-21 win Monday night.
Tennessee's defense held the Colts to 94 yards rushing.
With the game tied at 14 in the third quarter, Stephen Tulloch stopped Dominic Rhodes for a loss on fourth-and-1, setting up a short field and a 48-yard field goal for Rob Bironas. Nick Harper stepped in front of Marvin Harrison on fourth-and-2 during the Colts' next drive, and LenDale White scored a 1-yard touchdown to give the Titans a 24-14 lead.
"[The fourth down stops] were huge," defensive tackle Albert Haynesworth said. "You saw the classic Peyton with his 'Oh my God, I can't believe we missed that' [face]. We want to frustrate him as much as possible and we love seeing that. That really took a little bit out of him."
The Titans struggled to sack Manning playing without Pro Bowl defensive end Kyle Vanden Bosch, who was inactive with a groin injury. Haynesworth came closest, knocking Manning to the ground twice an instant after he released the football.
"I was trying to hit him as much as possible and get in his face. He was getting rid of the ball quick," Haynesworth said.
Said Tony Brown: "We know that it's hard to get to Peyton. We just tried to knock him off his rhythm and we did that. It's hard to get a sack on Peyton."
Rhodes found room to run at times, finishing with 70 yards on 17 carries, but Brown and the Titans tackled him behind the line of scrimmage several times and the Colts had little success in short-yardage situations. Indianapolis' best drive started the third quarter with a touchdown as the Titans trailed 14-6 behind a balanced set of play-calling. Tight end Dallas Clark found space in the middle of the defense, catching seven passes for 94 yards and two touchdowns. Yet Manning and the Colts' offense mustered only a late cosmetic touchdown after their initial second-half drive.
"The first drive of the second half, they had us off balance... but we held tough," linebacker Keith Bulluck said.
STREAK OVER: Vanden Bosch started 54 straight games before Monday night.
The two-time Pro Bowler warmed up on two occasions but couldn't play. Vanden Bosch initially injured his groin during the first half of a victory at Baltimore Oct. 5. He started against Kansas City last week but left the game after three plays and did not return.
Dave Ball was announced as the starter in his place at right defensive end, but was injured on the opening kickoff. Jacob Ford started in his place.
"You can't let that be on your mind when you're playing," Haynesworth said of Vanden Bosch's absence.
BIRONAS TIES RECORD: Rob Bironas tied a franchise record in the second quarter when he made his 20th-straight field goal.
Bironas hit from 44 yards out to tie the record set by Al Del Greco from 1998-99. A lone firework exploded an instant before the ball was snapped, causing head coach Jeff Fisher to glare toward the sound, but Bironas made the kick anyway.
He missed a 43-yard field goal in the second quarter, ending his streak at 20. Bironas made 19 straight last year before missing a 53-yard field goal against Houston. Bironas made 3-of-4 field goals against the Colts.
COMMANDING LEAD: Tennessee remains perfect at 7-0 while the rest of the division is 3-4, four games back. The Titans were quick to dismiss questions about building an insurmountable lead with nine regular-season games left on the schedule. Still, a national audience saw the Titans beat the reigning AFC South champions.
"Until the Indianapolis Colts haven't won the division, it doesn't change anything," White said. "Right now we have a good lead on them, but things can happen. We definitely don't want that, we're not praying for that, but it's not over until the season's up."
Bulluck had a different take.
"They're not the team to beat any more. I think we made a statement tonight within the division. The Colts were the team to beat and I think right now the Titans are the team to beat in the AFC South."
HOPE PICKS TWO: Chris Hope became the third Titans defensive back to record two interceptions in a game this year, intercepting Manning twice.
"The first one I was breaking on it and Vinny [Fuller] got a hand in -- he played a great game," Hope said.
Hope's second interception set up the final touchdown of the night, a 16-yard run by Chris Johnson.
Cortland Finnegan and Michael Griffin also had two-interception games earlier this year.
CODE BLUE: Tennessee celebrated their first home Monday Night Football game in four years with a "Code Blue," blanketing LP Field with the color in celebration.
The Titans gave out 68,000 light blue T-shirts promoting the event. Several colleges have popularized similar events -- Georgia had a "blackout" earlier this year and Penn State had a "whiteout" -- but the "Code Blue" is believed to be the first of its kind in NFL history. The team wore its powder blue pants and matching jerseys and the cluster of restaurants and concessions in the end zones, usually red, were given a fresh blue facade.
"I guess it goes without saying this was a great night for Nashville," head coach Jeff Fisher said.
Adding to the festive atmosphere, Hank Williams, Jr., sang the national anthem and riled up the fans before the game. The Paris, Tenn., country singer has become synonymous with Monday Night Football. His introduction, based on his hit song "All My Rowdy Friends are Coming Over Tonight," has played on Monday Night Football Telecasts since 1989.
RING OF HONOR: The Titans inducted QB Steve McNair, RB Eddie George and TE Frank Wycheck into the Ring of Honor during halftime Monday night. The trio will also be inducted into the Titans/Oilers Hall of Fame.
All three gave short speeches to the crowd at LP Field and received large plaques.
"It was an honor and a pleasure... to give my heart and soul to you all right here in this stadium," Wycheck said.
The Titans/Oilers Ring of Honor was unveiled during the season opener against the Jacksonville Jaguars. The three players, all a part of the 1999 AFC Championship team, join 10 others in the Ring of Honor: Titans owner K.S. "Bud" Adams, Jr., Elvin Bethea, George Blanda, Earl Campbell, Mike Holovak, Ken Houston, Mike Munchak, Jim Norton, Warren Moon and Bruce Matthews.