In an enthralling opening to the first leg of this last 16 encounter, Vitolo volleyed in his fifth goal in four games after just 13 seconds.
After Luciano Vietto had hit the bar for Villarreal, a clinical Sevilla side moved further ahead through Stephane Mbia.
Vietto's close-range finish in the 48th minute gave Villarreal hope, but that was extinguished almost instantly due to Kevin Gameiro's emphatic effort.
A frustrated Marcelino was sent to the stands as his side slipped to only a second home defeat in 13 matches, while Sevilla made it three straight away wins in all competitions.
Marcelino was without Giovani dos Santos and made a number of changes, with Vietto among those drafted in, while Gameiro started for Sevilla as Carlos Bacca was dropped.
The visitors made a stunning start as a long ball found Gameiro and he flicked the ball into the path of Vitolo, who coolly controlled before volleying past Sergio Asenjo.
In a breathless opening, the hosts should have equalised when Ikechukwu Uche's low cross found Vietto, but he shot against the crossbar and an off-balance Denis Cheryshev could not guide the rebound on target.
Cheryshev then combined neatly with Vietto before firing goalwards from 20 yards and forcing Sergio Rico into a low save.
The game continued at a frantic pace, with Vicente Iborra heading at Asenjo and Vietto forcing Rico to save with his feet, and the visitors moved further ahead after 26 minutes when a left-wing cross was met by a bullet header from Mbia.
Sevilla should have put the game to bed five minutes before the break, Aleix Vidal hitting the crossbar following a swift counter-attack.
The opening exchanges of the second half also proved eventful, with Villarreal notching a deserved goal in the 49th minute after Sevilla failed to clear Cheryshev's shot. The ball found its way to Vietto, who prodded home from close range.
However, Villarreal's ecstasy turned to agony within two minutes as a long free-kick from Sevilla bounced loose to the unmarked Gameiro and he lashed home emphatically to restore his team's two-goal cushion.
It was too much for former Sevilla coach Marcelino, who was sent to the stands after 53 minutes, but Villarreal fought valiantly to maintain their unbeaten run in this season's competition and substitute Joel Campbell saw a volley wonderfully kept out by Rico on the hour.
A thunderous effort from Cheryshev after 68 minutes flew just wide and Rico ensured his side retained a comfortable advantage by saving two point-blank headers from Gerard in the final minute.
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