It was also the first under new general manager Chris Ballard, the former Kansas City Chiefs' Director of Football Operations, following the dismissal of Ryan Grigson.

After an ineffective performance by backup Scott Tolzien in Week 1 against the Rams, the Colts put Jacoby Brissett as their starting quarterback for the rest of the season.

Running backs (RB) Wide receivers (WR) Tight ends (TE) Defensive linemen (DL) Defensive backs (DB) Special teams Reserve Note: Intra-division opponents are in bold text.

In a battle of 0–2 teams, the Colts took a 28–14 lead at halftime, then halted a Browns comeback in the second half.

Despite allowing the 49ers to rally from a 23–9 deficit in the 2nd half, the Colts won in overtime on an Adam Vinatieri field goal to improve to 2–3 while going 1-3 against the NFC West.

Despite leading 19–9 in the third quarter, the Colts were outscored 27–3 the rest of the way, resulting in their first loss to the Titans since 2011, snapping their 11-game winning streak in the series.

Despite leading for a good portion of the game, a late pick 6 by Jacoby Brissett did the Colts in, as they fell to 2–6.

Despite a 16–6 lead in the 3rd quarter, the Titans managed to pull off the comeback to win 20–16 and send the Colts to 3–8.

[15] The Colts and Bills played a low-scoring affair, tied at 7 by the end of regulation thanks to a fourth quarter touchdown pass from Jacoby Brissett to Jack Doyle.

However, LeSean McCoy managed to win the game for the Bills with a 21-yard touchdown run in overtime.