Ernesto Valverde's side, who only registered their first league win against Malaga last weekend, were quickly in front at the Madrigal when Joseba Llorente battled through to score.
Robert Pires, Giuseppe Rossi and Llorente again netted in quick succession just after the break and Cani arrived at the back post to net the fifth at the end.
Villarreal, who were bottom after seven games, climbed to 13th with nine points from nine outings.
"There was pressure on us to win and in the end we logged a 5-0, but it wasn't easy," Valverde told reporters.
"It's a good result but we have to keep our feet on the ground."
Champions Barcelona continued to top the standings with 23 points despite being held to a 1-1 draw at Osasuna on Saturday, defender Gerard Pique scoring an own goal in the last minute.
Real Madrid are a point back in second after a Gonzalo Higuain brace earned them a 2-0 home win over Getafe with 10 men, and Sevilla are third with 19 points having seen off Andalucian rivals Xerez 2-0.
Valencia are fourth with 18 points, one ahead of Real Mallorca in fifth after both won on Sunday.
David Navarro's back-post header after 68 minutes helped Valencia squeeze past struggling Malaga 1-0, and they had the crossbar and goalkeeper Cesar to thank in the closing stages.
Malaga remained rooted to the foot of the table with four points.
Cameroon striker Pierre Webo earned surprise packages Mallorca their fifth consecutive home win in a 1-0 victory over Racing Santander, and they climbed above Deportivo La Coruna who were held 1-1 at home by north-coast rivals Sporting Gijon.
