Jadon Sancho made the breakthrough in the 17th minute before Ronaldo netted in the latter stages of the first half, and the victory has moved Erik ten Hag's side into second spot in Group E, three points behind leaders Real Sociedad, who recorded a 2-1 win over Ononia in the section's other fixture.
The home side had the first half-chance in the 12th minute when Mouhamed Diop found himself free outside the Man United box, but his effort was always moving high of David de Gea's goal.
Ronaldo had a penalty shout in the 15th minute when he went down inside the box under pressure from Gaby Kiki, but the referee was not interested.
Man United made the breakthrough in the 17th minute when Sancho - left out of the latest England squad - worked space inside the Sheriff penalty area before picking out the bottom corner with a smart finish.
Iyayi Atiemwen struck wide of the the away side's goal in the 23rd minute, with Sheriff looking dangerous when they were able to work space in forward positions.
Ronaldo was next to try his luck, with the Portugal international breaking into a shooting position after smart work from Antony, but his effort was always rising over the crossbar.
Sancho came within inches of scoring a second for Man United late in the first half, with his effort cleared off the line by Stjepan Radeljic.
The Red Devils were awarded a penalty in the 39th minute when Diogo Dalot was felled by Patrick Kpozo, and Ronaldo stepped up to score his first goal of the campaign.
Bruno Fernandes came close to a third for Man United early in the second period, but his low effort was saved by the home side's goalkeeper.
Christian Eriksen delivered a brilliant cross towards Ronaldo shortly later, but Radeljic was on hand to make a fine clearance, with the Portuguese waiting to score his second.
Sheriff struggled to carry a threat throughout the 90 minutes, with the visitors, who introduced Casemiro, Luke Shaw, Anthony Elanga, Harry Maguire and Alejandro Garnacho, hardly needing to break out of second gear on a comfortable night.