The Colts started 9-0 but finished the season with a 12-4 record and got the third seed in the playoffs. Manning had a good season, throwing for 31 touchdowns, 4397 yards, and leading the NFL with a 101.0 Quarterback rating. In addition, by throwing 31 TD passes and only 9 interceptions he became the second quarterback in league history (the other being Donovan McNabb) to throw 30 touchdowns and fewer than 10 interceptions in a single season.

Manning's Colts defeated the Kansas City Chiefs in the first round of the playoffs on January 6 by the score of 23-8. On Saturday, January 13, 2007, the Colts won their Divisional Playoff game against the Baltimore Ravens by the score of 15-6, in which all of the Colts' points were scored by Adam Vinatieri, whose 5 field goals tied an NFL record. The Colts played the New England Patriots on Sunday, January 21, 2007 for the AFC Championship. The Colts (#3 seed) had home field advantage because they beat the Patriots during the regular season (tiebreaker rule). The Colts defeated the Patriots for the AFC Championship by a score of 38-34, after coming back from an 18 point deficit, the largest ever overcome in a conference championship (NFL record).

On February 4, Manning led the Colts to a 29-17 victory over the Chicago Bears in Super Bowl XLI (247 passing yards on 25 of 38 passes; 1 TD pass and 1 INT) and was voted the Super Bowl MVP. According to NewsMax.com Manning, a seven-times All-Pro quarterback slammed by his critics for failing to win when it matters, exorcised his big-game demons with the win. "In years' past when our team's come up short, it's been disappointing," he told reporters. "Somehow we found a way to have learned from some of those losses and we've been a better team because of it."

In 2005 the Colts had a greatly improved defense over that of recent years. In week 15, the Colts had a perfect 13-0 record, and had secured the AFC South, home field advantage throughout the playoffs, and a first round bye. Nevertheless, Tony Dungy made the decision to play all of his regular starters against the Chargers in the hopes of keeping his team sharp for the playoffs. However, the Colts played a sub-par game against the Chargers and fell short of the win; the score was 26-17. Manning finished the season with 3,747 passing yards, the first time he had thrown for under 4,000 yards since his rookie season of 1998, largely due to the fact that Manning sat out much of the final two games with the top AFC seed clinched.

On January 15, 2006, the Pittsburgh Steelers visited the RCA Dome for the second AFC divisional playoff game of the 2005 season. The Steelers shocked most fans and analysts by gaining a 14-3 lead by halftime. In the 4th quarter the Colts were almost able to pull off an improbable comeback, after a series of unlikely (and controversial) events. With only a few minutes left in the game, Manning threw what looked to be the game-ending interception to Troy Polamalu, but the interception was overturned (a call the NFL later admitted was incorrect). The Colts went on to score, and were able to get the ball back down three points near the end of the game. On 4th down Manning was sacked near his own goal line, and the game seemed to be over as the Steelers were one yard from a touchdown. On the play the ball was handed off to Bettis who fumbled the ball. It was picked up by Colts defender Nick Harper who appeared to have a clear path down the sideline for what might have been the game-winning score. However, he inexplicably cut to the center of the field where Steelers' quarterback Ben Roethlisberger was running backwards hoping to get into position to tackle. He managed to dive in front of Harper and tackle him by the leg, saving a touchdown. The Colts drove down the field from their own 42 yard line to the Steelers 27 yard line, before Mike Vanderjagt missed a field goal as time ran out. (It was the first time a 6th seeded team would eventually go on to win the Super Bowl when the Steelers won Super Bowl XL.)

Peyton came in second in voting for the 2005 MVP award to Shaun Alexander (19 to 13, out of 50 voters), ending his streak at two years. He was named the 2005 winner of the Walter Payton Man of the Year Award. He was also nominated for the 2005 FedEx Air Player of the Year Award, along with Tom Brady and Carson Palmer, the winner of the award. The two runners up were both also quarterbacks for the Pro Bowl that year

In 2004, Manning had one of the greatest regular seasons in NFL history, putting up 4,557 yards, a 121.1 quarterback rating, and 49 touchdowns, surpassing the record for TD passes in a season (4 held by Miami Dolphins quarterback Dan Marino for two decades.[2] His quarterback rating in 2004 also surpassed the previous single-season mark of 112.8 set by Hall of Fame San Francisco 49ers quarterback Steve Young. In addition to his individual achievements, Manning also led the Colts to a 12-4 record and their second consecutive AFC South division title. As a result, he was a near-unanimous selection for the 2004 NFL MVP in drawing 49 of 50 votes (Michael Vick received one vote), was named NFL Offensive Player of the Year respectively. However, the Colts' 2004 season ended in Foxborough for a second straight year with a 20 - 3 loss in the AFC Divisional Playoff game against New England when Manning played his worst game of the year, recording a season-low passer rating of 69.3 and posting a season-low 3 points of offense. It was Manning's seventh consecutive loss to the Patriots in Foxborough, MA. The Colts' three points were their lowest single game point total since their opening game of the 2003 season