Marcelo, Isco, Luka Modric and Vinicius Junior earned recalls for Real, with Eden Hazard and Carlos Casemiro unavailable after testing positive for Coronavirus.
Los Che were behind after the opening quarter when Karim Benzema collected a low pass from the left by Marcelo to lean backwards before finding the top corner.
Valencia had the ball in the net from the penalty spot on the half-hour mark through Yunus Musah after Thibaut Courtois denied Carlos Soler with a double save. However, the goal was disallowed by the Video Assistant Referee (VAR) after an encroachment, leading to a retake which Soler made no mistake with to beat Courtois from 12 yards out.
Real were behind a minute to halftime when Raphael Varane helped a floating ball in the area from Maximiliano Gomez into his own net, with a review from VAR giving the all clear.
Los Che sealed a third goal six minutes from the interval as Soler bagged a second from the penalty spot after Marcelo sent Gomez on the deck in full view of the man in the middle.
Real conceded a third penalty on 61 minutes with another VAR intervention penalising Sergio Ramos for a hand used in the box, as Soler tucked away for his hat-trick.
Fresh faces on the path of Real three minutes later led to the introduction of Rodrygo and Martin Odegaard, with Asensio and Vinicius sacrificed as Los Blancos looked to restore some pride.
This did nothing to aid their quest with Javi Garcia's side running down the final minutes for a massive win over an old enemy.