Having lost their Group E opener at home to the Spanish side, Erik ten Hag’s side won four straight matches to wrap up a top-two finish with a match to spare.
Diogo Dalot and substitute Marcus Rashford headers put United on course for that latest Europa League win, with returning Ronaldo wrapping up a 3-0 victory to the delight of the Old Trafford faithful.
The 37-year-old had looked set to be frustrated on Thursday as he made his first appearance since refusing to come on against Tottenham last week and sitting out Saturday’s trip to Chelsea as punishment.
Ronaldo was booked for booting the ball away after seeing a second-half effort disallowed after Rashford had added to Dalot’s first-half opener, but he would finally score his 701st club goal in the 81st minute.
This victory sets up a key clash in Spain next Thursday, when United will attempt to usurp current pool leaders Real Sociedad in a Group E showdown.
If United fail in that quest, they will have to play in a knockout round play-off against one of the third-ranked teams from the Champions League group phase.
Keeping hope alive of topping the group was the focus at Old Trafford, where Alejandro Garnacho made his full debut and impressed to such an extent that he left to a standing ovation.
United were on top from the outset and the 18-year-old received applause from Ronaldo after producing a stepover and darting forward before seeing a cross to the veteran cut out.
The frontman powered a header over and Bruno Fernandes bent wide from 20 yards as the onslaught continued, with Ronaldo’s attempt to meet the stand-in skipper’s cushioned header then thwarted by Maxym Koval.
Sheriff’s goalkeeper denied Christian Eriksen from distance and Tyrell Malacia saw a fizzing low effort stopped before Sheriff threatened a shock opener.
There was collective intake of breath inside Old Trafford when Patrick Kpozo’s superb cross from the left just evaded Ibrahim Akanbi Rasheed in the box.
It would have been a huge moment in Sheriff’s history, never mind the game, and appeared to spark United into life.
Eriksen sent a corner from the left-hand side into the six-yard box, where Dalot directed home a header in the 44th minute.
That goal allowed Ten Hag to make a pair of changes at half-time.
Lisandro Martinez was replaced by Harry Maguire, who came on for his first United appearance since the trip to Moldova six weeks ago and Marcus Rashford replaced Antony.
The summer signing’s most discussed contribution from this match was his unnecessary showboating spins on the ball.
The one-way traffic continued as Eriksen struck a free-kick into the Stretford End, which was again collecting the ball after Ronaldo cut inside and struck narrowly wide from the edge of the box.
The 37-year-old stood with hands on hips in disbelief as ‘Viva Ronaldo’ began to echo around Old Trafford.
Further frustration followed for the Portuguese in the 61st minute as a move involving an exquisite Garnacho touch ended with him rifling home from close range, only to find out he had strayed offside.
Ronaldo was booked for kicking the ball away in anger.
Scott McTominay and Luke Shaw were introduced as United pushed for a second that the latter was key in, floating a fine cross from the left for fellow sub Rashford to head home in the 65th minute.
The World Cup hopeful saw a low shot pushed wide and Garnacho went close before leaving to applause from all inside Old Trafford.
Donny van de Beek came on for a rare appearance before Ronaldo gave fans the goal they had been waiting for. Initially denied by Koval when found by a Bruno Fernandes cross, he fired in the loose ball – his first Old Trafford goal since May.
There were further United chances but no goals as the clock wound down on a straightforward win.