Week 1 at Houston Texans (L 34–24): In a season-opening loss in Houston, Manning set career highs in pass attempts (57) and completions (40), throwing for 3 TDs and 433 yards, the fourth highest opening-weekend total ever. It was his 8th 400 yard passing game in the regular season, putting him in sole possession of 2nd place all time (Dan Marino, 13).
Week 2 vs. New York Giants (W 38-14): Manning played against his brother Eli in the second "Manning Bowl" on Sunday Night Football. Peyton outdueled his brother, throwing for 3 TDs, and 255 yards.
Week 3 at Denver Broncos (W 27-13): Manning passed for 325 yards, 3 TDs and no interceptions, marking the first time since 1960 a QB began a season with three consecutive games of at least 3 TD passes and zero interceptions.
Week 4 at Jacksonville Jaguars (L 31-28): Manning led two different game-tying TD drives in the fourth quarter, the last coming with 0:48 remaining. Jacksonville won the game on a 59 yard field goal by Josh Scobee on the final play. Manning passed for 352 yards and 2 TDs, surpassing John Elway for third all time in career passing yardage.
Week 5 vs. Kansas City Chiefs (W 19-9): Manning failed to throw a TD for the first time in 2010, but led the Colts on a game-winning drive in the 4th quarter (45th of his career) to hand the Chiefs their first loss of the season.
Week 6 at Washington Redskins (W 27-24): Manning passed for 307 yards and 2 TDs on Sunday Night Football. Including the playoffs, he has 68 career games with 300+ yards passing, moving him ahead of Dan Marino (67) for the most in NFL history.
Week 8 vs. Houston Texans (W 30-17): Manning passed for 268 yards and 2 TDs to improve to 9-0 at home against the Texans and 11-3 on Monday Night Football, the best Monday night record for any starting QB (min. 10 wins).
Week 9 at Philadelphia Eagles (L 26-24): Making his 200th consecutive regular season start, Manning passed for 294 yards and a TD, but was intercepted twice by Asante Samuel; the second coming with six seconds remaining as Manning tried to get the Colts in position for a winning field goal.
Week 10 vs. Cincinnati Bengals (W 23-17): Manning was held to a season-low 185 yards passing and no touchdowns, but improved to 7-0 as a career starter against the Bengals.
Week 11 at New England Patriots (L 31-28): Trailing 31-14 in the fourth quarter, Manning threw two TD passes to Blair White to make it 31-28. After driving to the New England twenty-four, Manning's first down pass was intercepted by James Sanders with thirty-one seconds remaining, securing the Patriot win. Manning passed for 396 yards, 4 TDs and 3 interceptions. The game marked the 22nd time Manning threw 4 TDs in a game, breaking a tie with Dan Marino for second-most all-time.
Week 12 vs. San Diego Chargers (L 36-14): Manning passed for 285 yards, 2 TDs, and 4 interceptions (two were returned for scores) in the largest margin of defeat at home in his NFL career. It was Manning's third career game with at least four interceptions (twice against San Diego). It was the fifth loss of the season for Indianapolis, ending the record streak of seven consecutive seasons with 12+ wins.
Week 13 vs. Dallas Cowboys (L 38-35 OT): For the second straight game, Manning finished with 2 TD passes and 4 interceptions (two returned for scores) as the Colts lost in overtime. The first interception return resulted in a 17-0 deficit in the first half. After taking a lead, the Colts trailed 35-28 late in the fourth quarter as Manning then engineered an 81-yard tying TD drive to force overtime. On their second possession in OT, Manning's third down pass was intercepted and returned to the Colts' 36 yard line. Dallas kicked the winning field goal six plays later. Manning threw for 365 yards.
Week 14 at Tennessee Titans (W 30-28): Manning bounced back on Thursday Night Football with an interception-free performance, passing for 319 yards and 2 TDs. He went over 4000 yards passing for the 11th time in a season, and tied Dan Marino with his 63rd regular season game with 300+ yards passing. Manning was named AFC Offensive Player of the Week for this game.
Week 15 vs. Jacksonville Jaguars (W 34-24): Manning passed for 229 yards and 2 TDs as the Colts prevented Jacksonville from claiming the AFC South with a victory.
Week 16 vs. Oakland Raiders (W 31-26): Manning passed for 179 yards and 3 TDs, and had a 27 yard rush on third-and-two in the fourth quarter to clinch a third straight win for the Colts.
Week 17 vs. Tennessee Titans (W 23-20): Manning led the 46th game-winning drive of his career as the Colts won the AFC South for the seventh time in eight years, and Manning became the first QB in NFL history to lead his team to nine consecutive postseason berths (2002-2010). It was the 208th consecutive regular season start of his career, breaking Gene Upshaw's record. For the season, Manning finished with a NFL record 450 completions on 679 attempts (2nd most in history), and a career-high 4700 yards passing.