Two goals apiece from Juan Mata and Roberto Soldado either side of an Ever Banega strike moved Valencia on to 60 points with seven matches left to play, six ahead of fourth-placed Villarreal.
Champions Barcelona are top with 84 points after coming back to beat Almeria 3-1 with a double from Lionel Messi on Saturday.
Barca maintained their eight-point advantage over chasing Real Madrid, who were 3-0 winners at Athletic Bilbao where Kaka scored two penalties. Real host the leaders next Saturday.
Valencia striker Soldado broke away to open the scoring in the 13th minute after an interception in midfield, and the hosts never allowed the visitors settle into their trademark passing game.
Spain winger Mata streaked away to double the advantage in the 55th and Villarreal crumbled with Thursday's 5-1 Europa League quarter-final first leg victory over Twente perhaps taking its toll. Banega scored from a Pablo Hernandez pull-back, Mata tapped into an open goal and Soldado lobbed Diego Lopez to complete the rout in the 76th.
REYES SKILL
Europa League holders Atletico moved closer to a return to the competition next season with a crushing win over Real Sociedad at the Calderon which could have been much bigger.
Filipe Luis opened the scoring with a fierce drive early on, Jose Antonio Reyes produced a wonderful piece of skill to set up Mario Suarez before the break and Argentina's Sergio Aguero sprinted clear to seal the points 12 minutes from time.
The holders were knocked out of this season's Europa League at the group stage in December.
Espanyol's steady slide out of contention for the European places continued on Sunday with a 0-0 draw at Hercules that saw them slip to eighth on 44 points. They host Atletico next weekend.
Sporting Gijon built on their shock win over Real Madrid at the Bernabeu last weekend by beating Osasuna 1-0.
David Barral pounced on an error to score in the second half as Sporting rose to 11th with 38 points. Hercules remain in the relegation places in 18th with 30 points, ahead of Malaga on goal difference, after Manuel Pellegrini's side drew 0-0 at home to 10-man Deportivo La Coruna.
Almeria are bottom with 26 points.
