Luis Enrique’s Barca were put to the sword by an Iago Aspas brace in Vigo while former striker Nolito was also on target along with John Guidetti in a resounding 4-1 win for the hosts.
Neymar’s 80th-minute strike proved of little consequence as Barca’s 100 per cent start to the league season came to an abrupt halt prior to Madrid’s hard-fought 2-1 victory over Athletic.
Cristiano Ronaldo went into the clash on the verge of a 500th career goal and three short of overtaking Raul as Real’s all-time leading scorer.
However, the Portuguese was surprisingly quiet at San Mames, with Karim Benzema stealing the show courtesy of a goal in each half either side of Sabin Merino’s equaliser.
Benzema has six goals in five appearances this term, with Wednesday’s double sending Rafael Benitez’s side top of the table.
At the other end, Sevilla’s troubles continued as they were beaten 2-0 at Las Palmas to stay rooted to the foot of the table.
Roque Mesa and Antolin Alcaraz ensured the hosts’ first win since returning to the top flight with the Europa League winners yet to get their season up and running.
Rayo Vallecano held off 10-man Sporting Gijon – claiming a 2-1 win thanks to goals from Roberto Trashorras and Javi Guerra – while Levante battled back from two goals down to claim a point against Eibar.
Borja Baston’s brace put the visitors in cruise control at the Estadio Ciudad de Valencia but, after Jose Luis Morales pulled one back, Deyverson picked the ideal time to open his account, scoring in the final minute to earn the hosts a dramatic draw.