Matthews appeared to injure his left shoulder after absorbing a hit from Jets defenceman Jacob Trouba early in the second period.
The 21-year-old cut to the front of the net with the puck and, as he attempted to shoot on goalie Connor Hellebuyck, Trouba went shoulder-to-shoulder with Matthews.
Matthews went to the bench on his own in apparent discomfort before eventually heading to the locker-room.
Nazem Kadri took his spot on the top line alongside Patrick Marleau and Kasperi Kapanen.
Matthews played 7:38 and had two shots on net before leaving.
After playing all 82 games in his rookie season, Matthews battled various injuries in 2017-18, including a problem with his right shoulder and a concussion that limited him to 62 games.
Matthews leads the Leafs in 2018-19 with 10 goals and 16 points in 10 games heading into Saturday’s contest.