The five-time Ballon d'Or winner had barely threatened until he fired past Geronimo Rulli at the back post to ease the mounting pressure on United manager Ole Gunnar Solskjaer with virtually the last kick of the game.
United were staring down the barrel of another embarrassing group stage exit from the Champions League after deservedly falling behind early in the second half to Paco Alcacer's smart finish.
Despite the result, there was little in the performance to quell the growing questions as to whether Solskjaer is the man to get the best out of a squad of supremely talented individuals that are yet to click as a collective.
Bruno Fernandes' stoppage-time penalty that ended up in the Stretford End condemned United to a 1-0 defeat to Aston Villa on Saturday, but Solskjaer showed his backing for the Portuguese midfielder by handing him the captain's armband in the absence of Harry Maguire.
Luke Shaw was also missing due to injury, while Aaron Wan-Bissaka was suspended after being sent off in the 2-1 defeat to Young Boys on matchday one.
A makeshift United defence looked as such in the first half as Villarreal wasted a host of chances to inflict more misery on the Red Devils after beating them in May to win the Europa League.
Arnaut Danjuma toyed with stand-in United right-back Diogo Dalot, but the Dutch winger firstly fired straight at David de Gea and was then denied by a brilliant finger-tip stop by the Spanish goalkeeper.
De Gea was the fall guy in the Europa League final as he was the only player of the 22 on both sides to fail to score in a marathon penalty shootout.
United fall behind
However, he has started the season in supreme form and was needed to save his side once more midway through the first half to turn Alcacer's header over.
Alcacer then fired wide with just De Gea to beat after an error from Raphael Varane and botched a two-on-one counter-attack with a poor pass to Yeremi Pino.
United did not heed their first-half warnings as eight minutes into the second period another promising break from Danjuma finally got the finish it deserved as Alcacer prodded through the legs of De Gea at the near post.
Telles was at fault for the opening goal as he played Danjuma onside.
But the Brazilian quickly made amends in spectacular fashion as he volleyed home Fernandes' free-kick from outside the area.
Solskjaer had named an extremely offensive line-up with Ronaldo flanked by Jadon Sancho and Mason Greenwood, and Paul Pogba alongside Fernandes in midfield.
But it was another night to forget Sancho since his £73 million move from Borussia Dortmund in July.
The England winger was easily kept in check by Juan Foyth before being replaced 15 minutes from time by Edinson Cavani.
The Uruguayan had a golden chance to instantly make himself the hero, but somehow headed wide with the goal gaping from Greenwood's perfect cross.
De Gea saved United once more five minutes from time in a goalmouth scramble to deny Moi Gomez and Boulaye Dia.
And Villarreal's profligacy in front of goal came back to haunt them as the all-time top goalscorer in Champions League history showed them how to finish.
Jesse Lingard turned a loose ball Ronaldo's way deep into stoppage time and his effort had too much power for Rulli.
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