It was their fourth season under head coach Frank Reich and fifth under the leadership of general manager Chris Ballard.

Despite having 7 Pro Bowlers and 5 AP All-Pros, the Colts failed to improve upon their 11–5 record from the previous season, after a Week 12 loss to the Tampa Bay Buccaneers.

The Colts were eliminated from the postseason in the final week of the season after a stunning loss to the 2–14 Jacksonville Jaguars and the Pittsburgh Steelers beating the Baltimore Ravens the same day.

Running backs (RB) Wide receivers (WR) Tight ends (TE) Defensive linemen (DL) Defensive backs (DB) Special teams Reserve The Colts' preseason opponents and results are mentioned as below: The Colts' 2021 schedule was announced on May 12.

Carson Wentz scored 3 total touchdowns and the defense forced four turnovers against the 49ers' offense.

The Colts blew another large lead and were defeated by the Titans in overtime after two costly interceptions from Wentz.

The Colts overcame several injuries and positive COVID-19 tests on their offensive line and defensive backfield to defeat the skidding Cardinals, improving them to 9–6 and putting them on the cusp of clinching a playoff berth.

In a shocking fashion, the Colts were upset by the 2–14 Jaguars thus ending their playoff hopes, as the Steelers won later that day.