Erik ten Hag named almost a first-choice line-up for the trip to Moldova, which has become bookended by postponed Premier League fixtures, with five changes from the defeat to Real Sociedad that opened their Group E campaign.
Marcus Rashford was the principle name missing, through injury, having missed out on the England squad earlier in the day.
It was a fellow United forward snubbed by Gareth Southgate who put the visitors in front, Jadon Sancho.
Following a rusty opening quarter of an hour in which Sheriff showed a reasonable amount of class and plenty of attacking intent, the Red Devils settled down and broke through via Christian Eriksen’s through ball, which Sancho used to turn his man and net via the far post.
The goal sparked United into some sort of life yet Sheriff, who had won their opener against Cypriot side Omonia, threatened with direct, high-tempo attacks. Nigerian striker Iyayi Atiemwen came closest after 21 minutes with a long-range drive that flashed wide of David De Gea’s near post.
Even with the hosts lacking end product, a second was likely needed and United began to bang on the door when goalkeeper Maksym Koval fluffed a clearance straight to Antony. Sancho was quickly found on the left but had his shot hacked off the line by Stjepan Radeljic.
Moments later, an even better chance was gifted to the away side as Patrick Kpozo clumsily caught Diogo Dalot from behind in the area. Cristiano Ronaldo stepped up to break his Europa League duck and send United into the break with a 2-0 lead.
Officially speaking, only 600 visiting fans attended on behalf of Manchester United yet many more of the 10,000-strong crowd were of a Red Devils persuasion, not least the masses filming the penalty from behind the goal or the vocal plenty joining Ronaldo in his celebratory cry of ‘Siu’ at his first goal of the season and 699th at club level.
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Casemiro replaced Scott McTominay at the break and United continued to try and build out their advantage, Bruno Fernandes having a low shot saved by Koval after a fine cross from Dalot.
Sheriff lacked any kind of spark in the second half and attention quickly turned to whether the visitors could thrash out a morale-boosting, statement scoreline - and perhaps another milestone for Ronaldo.
Instead, the Portuguese veteran placed a shot from 18 yards over the bar and failed to pick out Antony from a strong position down the right as the clock ticked down.
Luke Shaw, Anthony Elanga, Alejandro Garnacho and Harry Maguire were given runouts from the bench as United eased to their first points of the Europa League campaign in Chisinau.