Ronaldo, selected to lead the line as Erik ten Hag kept rotation to a minimum against the side that stunned Real Madrid in last season's Champions League, drilled home a first-half penalty to make it 2-0 to United, after Jadon Sancho had opened the scoring.
Having moved onto 699 club goals with his spot-kick, Ronaldo missed a chance to reach the 700 milestone after the break, but United produced a controlled performance to see out the victory.
United was in need of three points following last week's home defeat to Real Sociedad in their opening Group E game.
Although Sheriff started well, United took the lead with their first real attack 17 minutes in when Sancho turned on Christian Eriksen's pass and tucked a neat finish into the bottom-right corner.
Iyayi Atiemwen dragged wide of the bottom-left corner with David de Gea unsighted, before Stjepan Radeljic denied Sancho a second with a heroic goal-line clearance.
United were soon gifted an opportunity to double their lead by Patrick Kpozo, who was tempted into a foul by Diogo Dalot.
Ronaldo, who has had to settle for a substitute role in United's last four Premier League matches, lashed his penalty straight down the middle.
Radeljic was again on hand to clear as Ronaldo attacked the back post after the break, before Rasheed Akanbi almost caught De Gea out with a sumptuous lob from long range.
Ronaldo side-footed wide of the top-right corner from 18 yards out as a chance for his 700th club goal went begging, though United had little trouble in sealing a fifth win in their last six outings.