Real Betis continued Valencia's disappointing start to life under new manager Miroslav Djukic as Los Verdiblancos scored three times in the opening 35 minutes on their way to a 3-1 win.
Six of the previous seven meetings between the two had ended in victory for the home side and there seemed little doubt that run would end after Betis dominated the opening period.
Jorge Molina opened the scoring on 10 minutes after being fed by Salva Sevilla to fire home from inside the area.
Just 12 minutes later it was roles reversed for the second as this time Molina put Sevilla clean through on goal and he finished confidently past Diego Alves in the Valencia goal.
Sevilla doubled his tally for the evening 13 minutes later with a simple finish from Jorge Vadillo's cross and despite a late reply by Ricardo Costa for the visitors, Valencia slipped to a third consecutive defeat.
Elsewhere, Moudir El Hamdaoui made a sensational debut for Malaga as the Moroccan scored a hat-trick in the Andalusians 5-0 hammering of Rayo Vallecano.
The on-loan Fiorentina forward opened the scoring with a neat side-footed volley before squaring for Francisco Portillo to add the second before-half time.
And the former Ajax man completed his hat-trick with two more finishes from close range after Eliseu had fired into the top corner.
Espanyol moved up to fifth in the day's early game as Manu Lanzarote's controversial winner 14 minutes from time handed them a 1-0 win over Granada.
Referee Ignacio Iglesias Villanueva infuriated the home fans when he wrongly awarded Espanyol a free-kick inside the area for a backpass and Lanzarote dispatched the resultant indirect free-kick to continue the Catalans unbeaten start to the season.
At the bottom Getafe recorded their first win of the campaign thanks to a double from Miku.
The former Celtic forward scored either side of half-time to cancel out Roberto Torres' early opener.
Defeat leaves Osasuna still without a point after four games as they remain rooted to the foot of the table.