Manning played college football for the Ole Miss Rebels, winning the Maxwell and Johnny Unitas Golden Arm awards as a senior.

[3] The former, which saw the wild card Giants defeat a Patriots team that was the first to win all 16 regular season games, is regarded as one of the greatest sports upsets of all time.

[14][15] Manning entered college in the shadow of his brother Peyton, quarterback of the Indianapolis Colts, and his father, who was considered a "folk hero" at Ole Miss.

[43][44][45][46] The Rebels went on a six-game winning streak that included victories over major SEC opponents #24 Florida,[47] Alabama,[48] #21 Arkansas,[49] South Carolina,[50] and Auburn.

[78] All three would enjoy lengthy and successful careers with the teams that signed them and have been compared favorably to the 1983 NFL draft, which included Hall of Fame quarterbacks John Elway, Jim Kelly, and Dan Marino.

[82] In Week 15, against the Pittsburgh Steelers, he recorded his first multi-touchdown performance with 182 passing yards, two touchdowns, and one interception in the 33–30 loss in a duel with fellow rookie quarterback Ben Roethlisberger.

Manning led the Giants to a 2–0 record with victories against the Arizona Cardinals and New Orleans Saints,[88][89] before traveling to the West Coast for a test in a road game against the San Diego Chargers.

After losing a tough game to his brother Peyton and the Indianapolis Colts on opening day,[103] Manning and the Giants rebounded from a 24–7 fourth quarter deficit en route to a 30–24 overtime victory over the division rival Philadelphia Eagles in Week 2.

[104] Manning threw for a career-high 371 yards in the win with three touchdowns including a game-winning pass to Plaxico Burress in overtime to earn NFC Offensive Player of the Week.

[109] Playing against the Chicago Bears, Manning started well, but the Giants' offense was derailed by the loss of left tackle Luke Petitgout to a broken leg.

[126] Manning opened the 2007 season with an outstanding personal performance against the Dallas Cowboys, completing 28 of 41 passing attempts for 312 yards, four touchdowns, and an interception in New York's 45–35 loss.

[129] In week three, Manning got a come-from-behind victory as the Giants defense improved, pitching a shutout in the second half and stopping the Washington Redskins on a fourth and goal situation, winning the game 24–17.

'After a week of criticism in the New York media and being outplayed by Cowboys quarterback Tony Romo, Manning had a bounce-back victory against their conference Wild Card competitors the Detroit Lions.

[149] On January 13, 2008, in the Divisional Round Manning led the Giants to an upset victory over the heavily favored Dallas Cowboys, the number one seed in the NFC.

[153] In front of a record-setting American television audience[154] and on the strength of a late fourth quarter drive led by Manning, the Giants beat the 12.5 point-favored, undefeated New England Patriots 17–14.

The Ravens had come into the game with the league's third-ranked defense; nevertheless, Manning led the Giants to a decisive 30–10 victory, improving to 9–1, which included a 200-yard rushing effort by running backs Brandon Jacobs, Derrick Ward and Ahmad Bradshaw.

[176][177] In week 15, Manning and the Giants visited Texas Stadium, where Tony Romo battled through a lower back contusion and connected with nine different receivers, finishing 20-of-30 for 244 yards and two touchdowns leading the Dallas Cowboys to a 20–8 victory.

"[209] The Giants opened the 2011 season with a slow start, losing to the rival Washington Redskins 28–14– in an emotional game for both fanbases on the 10th anniversary of the September 11 attacks.

[210] Manning completed 18 of 32 passes for 268 yards but threw a costly interception in the third quarter to linebacker Ryan Kerrigan, who returned it for a touchdown and swung the momentum of the game.

[211] However, the Giants recovered and won their next three games, including over the arch-rival Philadelphia Eagles, where he had 254 passing yards and four touchdowns in the 29–16 victory to earn NFC Offensive Player of the Week.

[214] After a 6–2 start, including a 24–20 last-minute comeback by Manning over the New England Patriots that evoked comparisons to Super Bowl XLII,[215] the Giants entered a tough stretch of their schedule, facing off against the San Francisco 49ers, the New Orleans Saints and the Green Bay Packers, the respective eventual NFC West, South and North champions.

In the final regular-season game against the Dallas Cowboys, Manning threw for 346 yards and three touchdowns, giving the Giants the win, the NFC East title, and a playoff berth for the first time in three years.

[224] In the most-watched program in the history of United States television,[225] Manning once again led the Giants to an upset victory over the 2+1⁄2-point-favored Patriots 21–17, his second Super Bowl win and the fourth overall for the franchise.

For winning the Super Bowl, Manning and the Giants received a victory parade in Manhattan and were honored with symbolic keys to the city by Mayor Michael Bloomberg.

[281] Despite the loss, though, the Tampa Bay Buccaneers lost to the New Orleans Saints later that week 31–24, giving the Giants their first playoff berth since the 2011 season, when the team last won the Super Bowl.

[301][302] Following speculation that Manning would be released, new Giants head coach Pat Shurmur put these rumors aside by saying "I think what's important is we have a guy here who has helped this organization win Super Bowls.

Despite the pick, general manager Dave Gettleman said "the goal is for Eli to be our quarterback", while head coach Shurmur told Manning "it's your job to win games and keep [Jones] off the field".

When discussing his future plans, Manning stated that he did not wish to be a backup quarterback or pursue coaching opportunities with the team, as he felt he served both roles throughout the year and did not enjoy either one of them.

Manning said in 2007, "I am humbled by the work they do and am honored to make this five-year commitment to help raise funds to build this state-of-the-art clinic that will serve Mississippi families for years to come."

According to lawyer and journalist Michael McCann, Manning settled before trial in order to avoid damage to his marketability as an endorser and discipline from the NFL.