Despite a strong 5–2 start, the Colts would suffer a late-season collapse, losing 7 of their next 9 games, and were eliminated from playoff contention after a Week 15 loss to the New Orleans Saints.

This was partially a result of injuries to key skill players such as QB Jacoby Brissett, WR T. Y. Hilton, RB Marlon Mack and TE Eric Ebron.

Running backs (RB) Wide receivers (WR) Tight ends (TE) Defensive linemen (DL) Defensive backs (DB) Special teams Reserve The team was rocked by the decision August 24 by starting quarterback Andrew Luck that he would immediately retire from professional football due to chronic injury problems and the emotional and mental strain they had extracted.

Luck, the 2018 NFL Comeback Player of the Year, had been battling a mysterious and slow-healing leg injury, described by the team variously as a "calf strain" and a "high ankle issue.

[2] In a news conference Luck indicated that his recurring injuries had "taken my joy of this game away.... After 2016, I played in pain and was unable to practice, I said I wouldn't go through that again.

"[2] The team moved forward with former New England Patriots backup Jacoby Brissett, a third-year Colt, as its designated starting quarterback.

Adam Vinatieri missed a potential game-winning field goal late in the fourth quarter, resulting in a narrow two-point loss.