Manning was immersed in football from a very young age. His father, Archie Manning, was a star quarterback with the New Orleans Saints. (Younger brother Eli also became an NFL quarterback, and he led the New York Giants to a victory in Super Bowl XLII.) Peyton Manning was highly regarded as a high-school player and received a national Player of the Year award in his senior season. He attended the University of Tennessee, where he was the starting quarterback for four years. He earned the Sullivan Award as the country's top amateur athlete in 1996, was selected a first-team All-American in 1997, and finished his collegiate career in 1998 as Tennessee's career passing leader.

Manning was drafted first overall by the Indianapolis Colts in 1998. After struggling somewhat in his rookie season, he helped the Colts in 1999 to win the franchise's first division title since 1987. In 2000 Manning threw for 4,413 yards and 33 touchdowns to finish among the NFL's leading passers. Three years later he shared the league's Most Valuable Player (MVP) award with Steve McNair of the Tennessee Titans. Manning won the MVP honour outright in 2004 with a sensational performance that included 49 touchdown passes and a quarterback rating of 121.1, both NFL records for a single season (his touchdown record was broken by New England's Tom Brady (Brady, Tom) in 2007).

During the 2005 season, Manning led the Colts to victories in their first 13 games. Although considered one of the favourites to win the Super Bowl, the team lost in the divisional play-offs to the Pittsburgh Steelers. Some questioned Manning's ability to win a championship, but in the 2006 season he silenced his critics. He threw for 4,397 yards—the seventh time in his career he had passed for more than 4,000 yards, breaking Dan Marino's record—to lead the Colts to 12 wins during the regular season. After play-off victories over the Kansas City Chiefs, Baltimore Ravens, and New England Patriots, Manning helped the Colts defeat the Chicago Bears in Super Bowl XLI. For his performance, which included 25 completed passes for 247 yards, Manning was named the game's MVP. In 2008 he won the league MVP award a record-tying third time.