Nolito opened the scoring in the opening minutes and although Mikel San Jose leveled early in the second half for the home side, Sevilla controlled the game well and took advantage of defensive errors to virtually kill the tie off with further goals from Andre Silva and Wissan Ben Yedder.
Betis and Real Sociedad left everything to be decided for next week's return leg after a 0-0 draw in Betis' Benito Villamarin Stadium.
The best news in the game was the return to action of Real Sociedad midfielder Luca Sangali after he had suffered a minor stroke in October.
Wednesday saw Atletico Madrid draw 1-1 away to Girona, while Real Madrid defeated Leganes 3-0.
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