He missed the entire 2011 season after four neck surgeries weakened his right triceps and put his future in question.
Now 37, Manning regained his record when he threw for 400 yards and four touchdowns, including three in the fourth quarter. He surpassed the 50 TD passes Tom Brady threw in 2007 and led the Broncos (12-3) to the victory over the Texans (2-13) that extended Houston's franchise-record skid to 13 games.
Manning did it on a 25-yard pass to Julius Thomas with 4:28 remaining. Just 2½ minutes earlier, he tied the mark with a 20-yard pass to Eric Decker.
He entered the game with 47 and his first touchdown came on a 36-yard pass to Demaryius Thomas in the second quarter. The second was a 10-yard throw to Decker earlier in the fourth period.
Manning had previously established the record by throwing 49 touchdown passes in 2004.
"It's just amazing to be able to be a part of it," Denver center Manny Ramirez said. "Everything we see from Peyton, being prepared, it's worked for him."
The Broncos already had a spot in the playoffs, but their victory, combined with Kansas City's loss to Indianapolis, gave them the division crown.
"It's never fun to be on the opposite end of a record-breaking performance," Houston defensive end J.J. Watt said. "The guy is a heck of a football player and you give credit where credit is due. There is a reason the guy should be MVP this year."
Five things to know about the Broncos-Texans game:
ANDRE'S RECORD: Houston receiver Andre Johnson finished with four catches for 63 yards. He has 103 catches this season to reach 100 for the fifth time in his career, tying an NFL record for most seasons with at least that many receptions. Johnson entered the game needing one catch to reach the mark held by Denver's Wes Welker. He did it on a 33-yard reception in the first quarter. Johnson also had more than 100 receptions in 2006, 2008, 2009 and 2012.
"It's all fine and dandy," Johnson said of the record, "but I only play the game for one reason, and that's to win. It's a great thing to happen, but under these circumstances it really doesn't matter."
NO WELKER, NO PROBLEM: Welker missed his second straight game after sustaining his second concussion in four weeks on Dec. 8. But Manning still had a big day thanks to the strong play of Denver's other receivers. Decker led the Broncos with 10 receptions for 131 yards, and Demaryius Thomas had eight catches for 123 yards. Julius Thomas added six receptions for 78 yards.
Demaryius Thomas leads the team with 1,317 yards receiving, Decker has a career-high 1,261 and Julius Thomas 752, also a career-best.
SCHAUB'S LAST HOORAH IN HOUSTON? Matt Schaub started for the first time since Oct. 13 in place of the injured Case Keenum. He finished with 176 yards and one touchdown with two interceptions. Schaub, benched for Keenum after a terrible six games, admitted that he has thought about the possibility Sunday was his last game for Houston.
"It has definitely crossed my mind," he said. "I didn't want to think too far ahead, but I've played this game long enough to know how things work."
MILLER'S KNEE: The Broncos lost star linebacker Von Miller to a knee injury in the first quarter. Miller was able to walk off the field on his own after being hurt in the first quarter. Miller was the second overall pick in the 2011 draft and won Defensive Rookie of the Year honors. He was suspended for the first six games this season after violating the league's drug-abuse policy. He has started all nine games since his return and has five sacks.
Denver coach John Fox didn't have an update on Miller's condition after the game.
"They'll have tests," Fox said. "Anything until we get all of the tests will be purely speculation, so we will just wait until we hear something definitive."
KNOWSHON 1K: Denver's Knowshon Moreno had 11 carries for 76 yards on Sunday to reach 1,015 yards for his first career 1,000-yard rushing season and the 20th in franchise history. He also had two receptions for 26 yards to give him 507 yards receiving and make him the first player in Denver history to have 1,000 yards rushing and 500 yards receiving in a season.