Ousmane Dembele scored twice as Barcelona thrashed Villarreal 5-1 on Wednesday and edged closer to their first ever unbeaten season in La Liga.
But Real Madrid slipped to their only league defeat since February as a heavily-rotated side lost 3-2 away at Sevilla.
Lionel Messi volleyed in a sumptuous pass from Andres Iniesta at Camp Nou to put Barca three up at half-time after Philippe Coutinho and Paulinho had scored one apiece in the first 16 minutes.
The second period, however, belonged to Dembele, who capped an excellent individual display with two goals after the Frenchman's sensational run had also earlier set up Coutinho.
Villarreal managed a consolation when Pablo Fornals' shot deflected in off Nicola Sansone but any fears Ernesto Valverde's side would feel the effects of Sunday's 'Clasico' proved unfounded.
The league leaders moved 15 points clear of Atletico Madrid at the top while Villarreal stay sixth.
The Yellow Submarine are only three points ahead of Sevilla, however, who climbed back into the Europa League qualification spots with a well-deserved win over Real.
Zinedine Zidane said he wanted to maintain momentum ahead of their Champions League final against Liverpool on May 26 but Marcelo, Luka Modric and Cristiano Ronaldo were among those not even included in his squad.
Sevilla took full advantage as Wissam Ben Yedder, Miguel Layun and a Sergio Ramos own-goal put them three up, before Real substitute Borja Mayoral and a late Ramos penalty late gave Real a flatteringly close result.
Barca drew last weekend against Real, despite playing the entire second half with 10 men, and they now need only avoid defeat in matches away at Levante and home to Real Sociedad to complete the campaign as invincibles.
It would be the first time a team has finished a 38-game La Liga season unbeaten and the first in any format since Real avoided defeat in a division of only 10 teams in 1932.
"In the end we have scored two great goals, we are happy about this and we keep the run going," Valverde said.
Already crowned champions and winners of the Copa del Rey, Barca were controversially denied a guard of honour by Real but Villarreal were happy to perform the 'pasillo' as the hosts walked out before kick-off.
Valverde left some key players out, with Marc-Andre ter Stegen, Luis Suarez, Jordi Alba and Ivan Rakitic all missing from the starting line-up.
Messi, however, was included despite calls for the Argentinian now to be rested ahead of this summer's World Cup.
It meant a start for Dembele, who took his chance to impress with the stand-out performance of the night.
Dembele has endured a difficult debut season since joining for 147 million euros from Borussia Dortmund last year but Barcelona president Josep Maria Bartomeu said this week he is not for sale, and the 20-year-old delivered the perfect response.
"He is a player that has a lot of talent," Valverde said. "He is fast, he has this spark. All players need a process of adaptation and when you are young you still have to learn. Next year Dembele will be with us."
His run that set up Coutinho's opener in the 11th minute was arguably the moment of the match as he picked up the ball 10 yards inside Villarreal's half before driving past three defenders and unleashing a shot.
Villarreal goalkeeper Sergio Asenjo palmed the ball away but only to Coutinho, who was left with a tap-in.
Dembele then grabbed a late brace, his first an easy finish after a brilliant run by Rakitic down the right, his second coming after he sped away from Villarreal's defence, and lifted the ball over the helpess Asenjo.
French forward Ousmane Dembele (L) was the provider for Philippe Coutinho before hitting two, second-half, goals of his own at Camp Nou