Marcelino's side scored twice in injury time at the Estadio de la Ceramica last week to put themselves in the driving seat in this tie, with the Yellow Submarine once more conceding important late goals.
Valencia are one of the most in-form teams in Spain, boasting eight wins from their last 11 games in all competitions and suffering just one defeat in their previous 20 encounters.
Los Che beat Villarreal 3-0 when they hosted them in the league in January and another home win can be backed at 10/13 (1.77) with SportPesa.
The visitors are unbeaten on the road in the Europa League this season, having won away legs in previous knockout rounds against Sporting Club and Zenit St Petersburg. Another win for Villarreal is offered at 7/2 (4.50) with the draw at 11/4 (3.75).
Valencia are without midfielder Geoffrey Kondogbia and have doubts over top scorer Rodrigo Moreno, who missed Sunday's derby with Levante. Full-back Cristiano Piccini and goalkeeper Jaume Domenech are also doubts.
Villarreal received a boost this week with the return of full-back Jaume Costa and midfielder Javi Fuego from their respective injuries. Daniele Bonera, Bruno Soriano and Miguelon are still missing for the side from the province of Castellon.
Valencia have picked up a great deal of momentum in the last few weeks and tactically they are playing exactly how their manager wants them to.
The Mestalla outfit remain extremely tough to beat and boast La Liga's second-meanest defence, having conceded just 27 goals in 32 league games.
Valencia have also won their last four home European ties - two in the Champions League and two in the Europa League - and it would be a major shock if they failed to claim another triumph against their regional rivals who are out of form and defending poorly.
Furthermore, Marcelino's side are unbeaten in their last 19 matches at home in all competitions, winning six of their last seven, and they should be able to see off Villarreal on Thursday.