The Colts earned the first selection in the 2012 NFL draft due to a dismal 2–14 record in 2011 and used their first pick on Stanford quarterback Andrew Luck.

[1] The season marked the first for both head coach Chuck Pagano and general manager Ryan Grigson with the franchise.

[2][3] In the offseason, the Colts released quarterback Peyton Manning, who had been with the team since 1998, after having missed the previous season due to neck surgeries.

Offensive coordinator Bruce Arians served as interim head coach while Pagano underwent treatment for leukemia from week 5–16.

Eight days later (January 25), former Baltimore Ravens' defensive coordinator Chuck Pagano agreed to becoming the Colts new head coach.

The Colts drew first blood in the first quarter as Jerrell Freeman returned an interception 3 yards for a touchdown and a 7–0 lead.

In the 2nd quarter, the Bears took the lead as Brandon Marshall caught a 3-yard touchdown pass from Jay Cutler to make the score 14–7.

The Colts drew closer to shorten the lead to 3 with Donald Brown's 18-yard touchdown run to make the score 17–14.

However, the Colts moved further ahead as Vinatieri scored a 26-yard field goal, followed by Andrew Luck's 30-yard touchdown pass to Reggie Wayne for leads of 10–6 and then 17–6 at halftime.

In the 3rd quarter, the Jaguars were able to fire back as Maurice Jones-Drew ran in a touchdown from 59 yards out to cut the lead to 14–10.

But then the Jags were able to complete the comeback attempt 11 seconds later with Blaine Gabbert's touchdown pass to Cecil Shorts III (with a failed 2-point conversion) to make the final score 22–17.

In the 2nd quarter, the Packers increased their lead with Aaron Rodgers's 6-yard touchdown pass to James Jones to make the score 14–0.

However, the Packers pulled away as Aaron Rodgers connected with Randall Cobb for a 31-yard touchdown pass to take a 21–3 halftime lead.

However, the Packers again retook the lead as Rodgers found Jones again for an 8-yard touchdown pass (with a failed 2-point conversion) and led 27–22.

However, the Colts were able to capitalize the comeback victory with Luck's 4-yard touchdown pass to Reggie Wayne with the 2-point conversion successful and win the game 30–27.

However, the Jets pulled away as Sanchez found Jason Hill on a 5-yard touchdown pass to make the score 21–6 at halftime.

With the huge loss, the Colts fell to 2–3 while rookie QB Andrew Luck would have his first career game without a single touchdown pass.

In the fourth quarter, referee Tony Corrente unintentionally screamed out obscenities on the microphone, causing announcer Kevin Harlan to apologize to television audiences.