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2004 season: Second MVP

The 2004 Colts opened the season with a 27–24 loss to the Patriots, after Mike Vanderjagt missed a potentially game tying field goal in the closing seconds of the game.^[78] The Colts won their next four games including a 45–31 win over Green Bay in which Manning threw 5 touchdowns, earning him AFC Offensive Player of the Week honors, but then lost their next two games, to Jacksonville and Kansas City, despite Manning throwing for 840 yards combined in the two games.^{[40][79][80][81]} The Colts responded well, winning their next 8 games before losing their final regular season game to Denver, a game in which Manning played only the first series.^[82] During the month of November, Manning was named the AFC Offensive Player of the Week twice; once for his 5 touchdown performance in a 49–14 blowout of Houston and once for his performance in a 41–9 win at Detroit in which he threw 6 touchdowns in less than three quarters.^[83][84] Due to his performances in November, Manning earned AFC Offensive Player of the Month honors.^[40] He was named AFC Offensive Player of the Week for a fourth time in the week 16 game against San Diego^[40] where he led the Colts to a 34–31 victory after trailing by fifteen in the fourth quarter.^[85]

During the season, Manning threw for 4,557 yards, had a record 121.1 quarterback rating and 49 touchdowns, which was also a record (since broken).,^[39][86] He was selected as the 2004 NFL MVP drawing 49 of 50 votes, was named NFL Offensive Player of the Year and was named the Best NFL Player at the ESPY Awards for the second consecutive year; Manning also received the ESPY Award for Best Record-Breaking Performance for his 49 touchdown passes.^[36][75] The Colts finished the season with a 12–4 record and their second straight AFC South title. They were the third seed in the AFC.^[87] Three Colts receivers had 1,000 yards and 10 touchdowns that season.

In the Wild Card game against Denver, Manning passed for 458 yards and 4 touchdowns.^[88] However, the Colts' 2004 season ended in Foxborough for a second straight year with a 20–3 loss against New England, when Manning recorded a season-low passer rating of 69.3. It was Manning's seventh consecutive loss to the Patriots in Foxborough and the Colts' three points were their lowest single game point total since their opening game of the 2003 season.^[89] Manning was named a Pro Bowl starter; in the Pro Bowl, he threw 3 touchdowns in a 38–27 victory and was named the game's MVP.^[90] Manning was also a unanimous First-team All-Pro selection.^[91]