The victory ended the Broncos' 17-game regular-season winning streak in the first game Manning played against his former team since being released in March 2012.
Manning finished 29 of 49 for 386 yards with three TDs and one interception. He was sacked four times and tried desperately to rally the Broncos late.
But the Colts (5-2) took advantage of his and Denver's uncharacteristic mistakes.
Luck converted an early fumble into a TD pass. Indy got nine points out of a second-quarter strip sack, and Luck scored on a 10-yard run in the third quarter, a drive helped by a series of defensive penalties. When the Broncos (6-1) finally had a chance to tie it, Manning was intercepted.
Indianapolis has not lost consecutive games under Luck.
CHIEFS 17, TEXANS 16
KANSAS CITY, Mo. (AP) — Jamaal Charles ran for 86 yards and a touchdown, Alex Smith also ran for a score and the scrappy Chiefs held off the banged-up Houston to remain unbeaten.
The Chiefs were forced to punt the ball to Houston with 1:46 left in the game. But after Case Keenum threw an incompletion on first down, the young quarterback was stripped by linebacker Tamba Hali at his 2. Derrick Johnson recovered the fumble for the Chiefs.
Smith simply kneeled from there as time ran out, allowing Kansas City (7-0) to extend the second-best start in franchise history. The 2003 team began the season 9-0.
Keenum, making his first NFL start in place of the injured Matt Schaub, threw for 271 yards and a touchdown for the Texans (2-5). But he didn't get much help from his run game after Arian Foster left in the first quarter with a hamstring injury and did not return.
REDSKINS 45, BEARS 41
LANDOVER, Md. (AP) — Roy Helu's third touchdown, a 3-yard run with 45 seconds to play, lifted the Redskins.
Robert Griffin III completed 18 of 29 passes for 298 yards with two touchdowns and one interception for the Redskins (2-4), who have both of their wins against backup quarterbacks. This time it was Josh McCown, who entered in the second quarter after Jay Cutler left with a groin injury.
Griffin also ran 11 times for a season-high 84 yards against a defence depleted by injuries, but the breakout performance came from rookie tight end Jordan Reed, who caught nine passes for 134 yards and one touchdown.
McCown, playing in a regular-season game for the first time since the 2011 season, completed 14 of 20 passes for 204 yards with one touchdown. Matt Forte rushed for three touchdowns, Alshon Jeffrey had 105 yards receiving, and Devin Hester tied Deion Sanders' NFL record for return touchdowns with an 81-yard put runback for the Bears (4-3).
JETS 30, PATRIOTS 27, OT
EAST RUTHERFORD, N.J. (AP) — Nick Folk kicked a 42-yard field goal with 5:07 left in overtime. Folk got a second chance after he missed a 56-yarder moments earlier. But Chris Jones was called for unsportsmanlike conduct for pushing a teammate forward to try to block the kick, a new NFL rule.
New York, given new life, ran the ball three times to set up Folk's winner.
Geno Smith threw a touchdown pass and ran for another score as the Jets (4-3) topped Tom Brady and the Patriots (5-2). New England tied it at 27 with 16 seconds left in regulation on Stephen Gostkowski's 44-yard field goal.
New England had defeated New York in six straight regular-season meetings, and saw its 12-game winning streak against the AFC East end.
STEELERS 19, RAVENS 16
PITTSBURGH (AP) — Shaun Suisham drilled a 42-yard field goal with no time remaining. Suisham's fourth field goal of the day pushed the Steelers (2-4) to their second straight win.
Ben Roethlisberger completed 17 of 23 passes for 160 yards and a touchdown. He hit Antonio Brown for a pair of big gains on Pittsburgh's final drive, putting Suisham well within range to win it. Running back Le'Veon Bell ran for a season-high 93 yards on 19 carries.
Joe Flacco passed for 215 yards and a touchdown, but couldn't stop the defending Super Bowl champions (3-4) from losing for the third time in their last four games.
PACKERS 31, BROWNS 13
GREEN BAY, Wis. (AP) — Aaron Rodgers guided an undermanned offence with 260 yards and three touchdowns, and Eddie Lacy ran for another score.
Lacy finished with 82 yards, while tight end Jermichael Finley had a 10-yard touchdown catch in the first quarter before leaving with a neck injury. The team said he had movement in his extremities.
Green Bay (4-2) won its third straight game.
Rodgers finished 25 for 36 in methodically carving up Cleveland (3-4) despite already being without two of his top targets in injured receivers James Jones and Randall Cobb.
The defence took care of the rest against struggling quarterback Brandon Weeden, who was 17 for 42 for 149 yards. The Browns' Jordan Cameron caught a 2-yard touchdown pass in the fourth quarter.
49ERS 31, TITANS 17
NASHVILLE, Tenn. (AP) — Colin Kaepernick threw for 199 yards and ran for 68 and a touchdown. The 49ers (5-2) won their fourth straight before heading to London for a game with winless Jacksonville by jumping out to a 17-0 halftime lead. Frank Gore also ran for a pair of 1-yard TDs as San Francisco cruised.
Tramaine Brock also intercepted a pass, Justin Smith had two of the 49ers' three sacks and Kassim Osgood recovered a muffed punt for a TD.
The Titans (3-4) lost their third straight even with Jake Locker starting after missing two games with a sprained right hip and knee. Locker threw for 326 yards with two TD passes in a fourth-quarter spurt that came up short.
BENGALS 27, LIONS 24
DETROIT (AP) — Mike Nugent's 54-yard field goal as time expired lifted the Bengals. The AFC North-leading Bengals (5-2) won a game for the second straight week by the same score thanks to Nugent's right foot. He made an overtime kick to give Cincinnati a win after it blew a 14-point, fourth-quarter lead at Buffalo
The Lions (4-3) looked like they did enough to send the game to OT, but rookie Sam Martin shanked a punt just 28 yards to midfield in the final minute.
Andy Dalton, who threw three touchdown passes, took advantage with two short passes to set up the winning field goal.
Detroit's Matthew Stafford connected with Calvin Johnson on two of his three TD passes.
COWBOYS 17, EAGLES 3
PHILADELPHIA (AP) — Tony Romo threw for 317 yards and one touchdown and the Cowboys overcame a sluggish start to take sole possession of first place in the NFC East.
Two teams that averaged a combined 58 points per game and allowed a combined 55 totalled 13 punts in a first half that ended with Dallas (4-3) leading 3-0. It was more two inept offences than two dominant defences.
The Eagles (3-4) have lost a franchise-worst nine straight games at home. Their last win at the Linc was over the New York Giants on Sept. 30, 2012.
A Cowboys defensive line missing three of its projected starters pressured and harassed Nick Foles before sending him to the sideline with a head injury on the last play of the third quarter.
FALCONS 31, BUCCANEERS 23
ATLANTA (AP) — Matt Ryan threw for 273 yards and three touchdowns, including two to Jacquizz Rodgers, and the Falcons snapped their three-game losing streak.
Harry Douglas had seven receptions for a career-best 149 yards, including a 37-yard touchdown catch, for the Falcons (2-4). Douglas flourished as Ryan's No. 1 receiver with Julio Jones out for the season and Roddy White inactive for the first time in his nine-year career due to hamstring and ankle injuries.
Falcons safety William Moore sacked Mike Glennon to force a fumble on Tampa Bay's first possession. Safety Thomas DeCoud returned the fumble recovery 30 yards for a touchdown.
The Buccaneers (0-6) controlled the ball in the fourth quarter, but managed only two field goals by Rian Lindell.
BILLS 23, DOLPHINS 21
MIAMI GARDENS, Fla. (AP) — Mario Williams forced a fumble when he sacked Ryan Tannehill with less than three minutes left, setting up the winning field goal. Dan Carpenter, released in August after five seasons with the Dolphins, beat his former team by making a 31-yarder with 33 seconds to go.
Rookie Nickell Robey returned an interception 19 yards for a touchdown on the third play of the game to help the Bills build an early 14-0 lead, but they had to rally after Brandon Gibson caught his second touchdown pass of the game to put Miami ahead.
The injury-plagued Bills (3-4) ended a streak of six consecutive road losses, including two this season, while Miami (3-3) lost its third game in a row.
PANTHERS 30, RAMS 15
CHARLOTTE, N.C. (AP) — Cam Newton completed 15 of 17 passes for 204 yards and a touchdown in a heated game.
The Rams (3-4) lost their cool with several personal foul penalties — and then lost quarterback Sam Bradford to an apparent left knee injury late in the fourth quarter.
The extent of the injury was unknown and Bradford will undergo an MRI exam.
Bradford was running toward the sideline when he was pushed out of bounds by safety Mike Mitchell and came up holding his left knee. He was carted to the locker room.
Panthers quarterback Captain Munnerlyn intercepted Bradford on the game's first play and returned it 45 yards for a score. Bradford had a long TD pass called back on a penalty.
The Rams were flagged for five personal fouls and Chris Long was ejected for throwing a punch.
CHARGERS 24, JAGUARS 6
JACKSONVILLE, Fla. (AP) — Philip Rivers threw for 285 yards and a touchdown, Ryan Mathews ran for 110 yards and a score, and the surging Chargers (4-3) showed little, if any, issues with a short week, a cross-country flight and an early start time. And they played nothing like a team looking ahead to its bye week.
Then again, the Jaguars have made everyone look good.
Jacksonville (0-7) has lost every game this season by double digits, becoming the first team since the 1984 Houston Oilers to garner that dubious distinction. The Oilers lost their first 10 games that season by at least 10 points.
Rivers completed his first 14 passes, picking apart Jacksonville's defence with short throws and clock-eating drives. He finished 22 of 26.
Mathews topped the century mark for the second consecutive week.
AP NFL website: www.pro32.ap.org