Two goals were scored by Dembele, one Lionel Messi, Coutinho and Paulinho.
After a disappointing domestic season for both sides, it was the hosts who prevailed, with Wissam Ben Yedder shining on what was an incredibly entertaining night at the Ramón Sánchez Pizjuán Stadium.
Real Madrid tried to react but could not finish their chances.
No matter the professionalism and quality of Real's players there is little doubt they will have the Champions League final in the back of their minds in their closing La Liga games.
Real Madrid are likely to field a much changed starting eleven, with Cristiano Ronaldo nearly certain to be given the night off for the game with the side against whom he has scored more goals than any other.
Real Madrid were in trouble again just minutes later as Sergio Ramos had to react quickly to get across and block what looked like a promising effort on goal from Vasquez. Muriel got his head onto a long ball, setting up Ben Yedder who made it 1-0. They continued to control possession but struggled to penetrate the well drilled Sevilla defence.
Real Madrid have since turned their attention to Saturday's match against Celta, the last game this season at the Bernabéu. "But he was good, like the others, above all in the second half".
The game really kicked into life after Lucas Vasquez was brought down in the Sevilla box to earn Real Madrid a penalty.
Sergio Ramos had an event-filled evening on Wednesday night on his return to his former club.
Sevilla had been the better side in the opening quarter of the match, with Franco Vazquez sending a shot over the bar from the edge of the box and seeing another blocked by Ramos.
They grabbed themselves a first consolation goal after a delicious cross from Asensio was met by substitute Borja Mayoral.
A needless shove from Gabriel Mercado on Theo Hernandez then allowed Ramos to tuck away his second penalty, this time sending the goalkeeper the wrong way, but it came too late in the match for Los Blancos to nab a leveller.
However, Real did orchestrate something of a fightback late on.