The Oilers captain leads the NHL with 53 points (19 goals, 34 assists) in 33 games. He has not missed a game this season.
McDavid and forward Derek Ryan did not practice Tuesday after testing positive. They and defenseman Tyson Barrie will be out Wednesday because of protocol.
Edmonton (18-13-2) has lost four in a row and is 2-8-2 in its past 12 games.
"For us, there's no excuses," Oilers defenseman Darnell Nurse said. "We have to work our way out of this no matter who is in the lineup, who's out of the lineup."
Ryan McLeod will be the center on the top line with Zach Hyman and Jesse Puljujarvi.
"Kept [McDavid and Ryan] off (the ice) for precaution, and the way things are going here, this is a daily occurrence," Oilers coach Dave Tippett said Tuesday. "When you play in as many cities and there's different rules everywhere you go, it's crazy. They just tell me if he's positive, he's positive. When two of your four centermen are out and one of them is Connor McDavid, that is not good positive."
Edmonton will also be without forward Ryan Nugent-Hopkins, who was placed on injured reserve Wednesday with an undisclosed injury. He will miss his third game since he was injured in a 6-5 overtime loss to the New Jersey Devils on Dec. 31.
Maple Leafs center Auston Matthews expects to play after he tested positive Monday. Matthews, who had a negative PCR test Tuesday, was held out of practice as a precaution but took part in the morning skate Wednesday.
"I feel great. Didn't have symptoms or anything," Matthews said. "Plan on playing. Should be fresh. ... Just trying to prepare as best as possible and make sure I'm ready. Obviously it's not ideal taking two days off skating and practicing and that type of stuff. But I guess it is what it is and just kind of have to adjust long the way."
Matthews has scored 33 points (20 goals, 13 assists) in 28 games this season.
"If it seems he's ready to play, we're confident he can just drop right in from a system standpoint, a structure standpoint and familiarity with his teammates," coach Sheldon Keefe said Tuesday.
NHL.com staff writer Mike Zeisberger and independent correspondent Dave McCarthy contributed to this report
