Michael Carrick’s side don’t have long to dwell on their disappointing late 1-1 Premier League draw with fellow strugglers Tottenham over the weekend.
Per Goal, United are now expected to be without Mainoo, 21, and Shaw, 31, for their Champions League trip to Madrid.
Both were absent from training on Monday and are currently being monitored by the club’s medical staff to assess the severity of any potential issues.
A decision on whether they will even board the flight to Spain will be made late on the eve of the trip.
Mainoo has been key for Carrick so far this season, starting all but one of their six Premier League games.
Shaw, on the other hand, has struggled with small injuries since the summer and it’s understood Carrick has no intention of risking his only out-and-out left-back.
United head into the game hoping to build on their impressive 4-0 win over Sabah in their opener, while Atletico need to bounce back from a 2-1 loss to Liverpool.