With the game poised at 1-1 after extra-time, United goalkeeper David de Gea missed the decisive penalty after all previous 21 penalties had been scored, including by De Gea’s opposite number, Gerónimo Rulli.
The dramatic conclusion in Gdansk, Poland, also handed Villarreal coach Unai Emery a fourth Europa League trophy after he won three consecutive titles with Sevilla between 2014 and 2016.
United was the favorite to win the final having finished second in this season’s English Premier League, while Villarreal finished seventh in Spain’s La Liga.
But Villarreal defended stubbornly throughout the game, presenting United with few scoring opportunities.
It was Emery’s side which took the lead just inside the half-hour mark when Gerard Moreno connected with Dani Parejo’s free-kick — the first goal scored between these two sides after their previous encounters produced four goalless draws.
That was Moreno’s 30th goal of the season and saw Villarreal lead at halftime, although United almost equalized before the end of the half when Mason Greenwood’s cross was deflected off defender Raúl Albiol and into the hands of Rulli.
United did get an equalizer in the second half when Edinson Cavani reacted quickly following Paul Pogba’s blocked shot from a corner to poke the ball past Rulli.
Despite enjoying more chances throughout the second half, United was unable to take the lead, and the game went to penalties after an uneventful extra-time.
The penalty shootout, however, did provide drama.
The teams went toe-to-toe throughout before De Gea’s penalty was saved by Rulli, handing Villarreal a 1-1 (11-10) victory.
It was the sixth time in the past eight competitions that a Spanish side has won the Europa League, European football’s second-tier competition.