LenDale White ran for two touchdowns, Chris Hope intercepted Peyton Manning twice and the Titans routed the Colts 31-21 Monday night.
The Titans are now in control of the AFC South, four games ahead of Indianapolis, Houston and Jacksonville.
The Titans (7-0) have won an NFL-best 10 straight regular-season games, matching the second-best streak in franchise history. More importantly, Tennessee took control of the AFC South away from the team that has dominated this division in winning the past five titles.
The Titans have won three of four in the series, and linebacker Keith Bulluck said they made a statement with their latest victory.
"The Colts were the team to beat, and I think now, the Titans are the team to beat," Bulluck said.
Kerry Collins outmanaged Manning, throwing for 193 yards with no interceptions.
"We're trying to get where they've been," Collins said. "It was a big step for us tonight I think. We obviously got off to a good start, and to get one more against a division opponent is again real big at this time of year."
Jeff Fisher joined Tom Landry and Don Shula as the only NFL coaches to start 7-0 in their 15th season or later. He credited his defense for staying patient against Manning and his team for focusing on the Colts, not its surprising start.
"The season's still early, and there's a lot of games left," Fisher said. "Our focus was on the Colts and trying to prepare ... to try to find a way to beat them. That was the commitment that we made this week. We're not looking ahead. We'll now look ahead to next weekend. As far as the division and all that stuff's concerned, we're just trying to win ballgames right now."
Coach Tony Dungy had called this a must-win for Indianapolis to have any chance at winning the division, but now his Colts (3-4) have lost two straight in their worst start since Manning's rookie season. The Colts trail Tennessee by four games with nine games left and will host New England on Sunday night.
"It's going to make it doubtful for us to win the division, but ... we'll see what the last nine games bring," Dungy said. "If we play well and get ourselves on a streak and get going, we can be a playoff team. I think once you get in the playoffs, anything can happen as we've seen two of the last three years."
Manning had the Colts up 14-6 in the third quarter on two touchdown passes to Dallas Clark against a Tennessee defense that came in having allowed only one TD pass through the first six games.
But the Titans came up big after tying it at 14 with 3:21 left in the third.
The NFL's stingiest scoring defense stopped the Colts on fourth-and-short on consecutive drives at the end of the third and start of the fourth. Linebacker Stephen Tulloch stopped Dominic Rhodes behind the line on fourth-and-1 with less than a minute left in the third. Rob Bironas' second field goal, a 48-yarder, gave the Titans a 17-14 lead early in the fourth quarter.
On the Colts' next possession, Manning couldn't connect first with Reggie Wayne, who failed to pull in a pass one-handed. Then former Colts cornerback Nick Harper helped break up a pass to Marvin Harrison on fourth-and-2.
"You're there in the fourth quarter and you have to make the plays to win the ballgame, and when that time came, they made them all," Dungy said of the Titans.
Tennessee responded by driving 66 yards over 6:51, and White scored his second TD -- giving him 10 for the season. Hope picked off Manning again with 3:38 left. Rookie Chris Johnson scored his own TD on a 16-yard run and the sold-out crowd clad in Tennessee light blue began celebrating another win.
Manning scored on a 1-yard run with 1:17 left, but Titans safety Michael Griffin recovered the Colts' onside kick attempt that didn't travel 10 yards.
"I hope we can play a little ticked off," Manning said. "There's a healthy way to be angry and try to bounce back and do something about it. We had some chances tonight. We had the lead, and then just they made the plays in the second half, and we didn't."
Manning put the Colts up 14-6 with his second TD pass to Clark, a 19-yarder on their opening drive of the second half. That seemed like it might be enough on a night when all the Titans could manage were field goals.
They eventually got a little help from the Colts, who again were without Bob Sanders, the reigning Defensive Player of the Year, running back Joseph Addai and cornerback Kelvin Hayden.
The Titans drove 80 yards in 14 plays capped by White's 1-yard run on third-and-goal, assisted by an illegal contact penalty on Marlin Jackson with a flag coming a little late after Justin Gage had dropped a pass on third-and-5. Then Melvin Bullitt was called for pass interference on tight end Bo Scaife, putting the ball at the Indianapolis 18.
Tennessee then tied it at 14 when Collins rolled to his right and found fullback Ahmard Hall for the 2-point conversion.
NOTES:Hope had been the only starter in the Titans' secondary without an interception, and he turned in his first two-pick game of his career. ... The Colts are 29-10 in the AFC South. ... The Colts are 38-7 when Manning throws for two or more TDs. ... The Titans are 16-2 since 2006 when intercepting two or more passes. ... Tennessee did not allow a sack for a fifth straight game. ... Fisher tied Mike Ditka, his old coach when Fisher played for the Chicago Bears, for 22nd in NFL history with 127 career wins.