LenDale White ran for two touchdowns, Chris Hope intercepted Manning twice and the Titans routed the Indianapolis Colts 31-21 Monday night.
Chris Johnson rushed for 77 yards, including a 16-yard touchdown that sealed Tennessee's 31-21 victory.
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 grabbed control of the AFC South away from the team that has dominated this division in winning the past five titles.
Kerry Collins outplayed Manning, throwing for 193 yards with no interceptions.
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 in the loss column with nine games left and New England visiting on Sunday night.
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.
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.
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.