Matthews has missed the past two games due to a wrist injury, while Andersen has been out for four games with a lower-body injury.
Matthews leads the NHL in goals so far this season with 18 in 20 games, while also recording 13 assists. Andersen, meanwhile, is 11-3-2 in 16 appearances for the Maple Leafs with a 2.69 goals-against average and a .905 save percentage.
The North Division-leading Leafs (17-4-2) have shut out the Oilers (14-10) in each of the last two games. Puck drops on the third straight game between Toronto and Edmonton Wednesday at 8 p.m. ET/6 p.m. MT on Sportsnet.