Mathis recorded one tackle in Indianapolis' 20–7 loss to New York.
Mathis, who is the Colts' all-time sacks leader with 111, had not played since the team's 2013 playoff loss to the New England Patriots.
Mathis tore the Achilles tendon in his left foot in September 2014 while serving a four-game suspension for violating the league's ban on performance-enhancing substances.
The 34-year-old has two seasons left on a four-year, $36 million deal he signed in 2012.
With Mathis back, Indianapolis will likely improve on defense after giving up 23 points a game last season. The six-time Pro Bowler led the NFL with 19.5 sacks in 2013.
Wide receiver T.Y. Hilton also returned to the field for the Colts against the Jets on Monday. Hilton left last Sunday's loss to the Buffalo Bills in the fourth quarter with a knee injury. After rehabbing the injury during the week, he returned to practice on Saturday.
Hilton finished Monday night's game with four receptions for 45 yards.
The Colts (0–2) will play the Titans (1–1) in Tennessee on Sunday.
- Kayla Lombardo