Jose Mourinho's men progressed 3-1 on aggregate, and recorded their third undefeated game over Los Che in eight days, adding to their 5-0 Liga triumph over the weekend, and the 2-0 first leg win at the Bernabeu.
A tight first-half saw Madrid lose Iker Casillas to a freak injury, but a goal by Karim Benzema moments before the interval put the visitors in sight of the next round, and left Valencia needing four goals to recover.
Fabio Coentrao's 51st-minute red card and a free-kick from Tino Costa gave the hosts a glimmer of hope, but despite controlling the second half and a late dismissal for Angel Di Maria, Valencia could not muster a response as Los Blancos held on to advance to a last-four tie against either Malaga or Barcelona.
Benzema was the only change from the side that started the match at the Mestalla on Sunday, the France international replacing Gonzalo Higuain as the visitors’ lone forward.
Though Valencia started brightly, it was Madrid who threatened first, with Cristiano Ronaldo forcing a save at the near post from Guaita after latching on to Xabi Alonso’s precise through-ball.
However, the capital outfit were handed a blow with 17 minutes gone, as Casillas was forced off for Antonio Adan after a bizarre incident where he was accidentally kicked on the hand by Alvaro Arbeloa.
And Adan was soon called into action to stop a bullet header from Haedo Valdez, who had risen highest to meet Andres Guardado’s free-kick.
The Madrid reserve keeper would thwart the Paraguayan forward once more shortly after the half hour mark, this time blocking him from point blank range after the Valencia man had found space to shoot inside the six-yard area.
Madrid found themselves on the ropes somewhat, and attempted to wrest control of the game back from the hosts when Di Maria brought an acrobatic save out of Guaita with a testing drive from 25 yards out.
And in first-half injury time, Los Blancos put the tie virtually out of reach when a quick throw saw Alonso tee up Benzema, who lost Ricardo Costa and slotted home a vital away goal.
But Valencia were given hope six minutes into the second half when Coentrao was shown his second yellow card for a handball. The Portuguese’s infraction was doubly damaging, as Costa was able to steer the resulting free-kick under Adan to make it 1-1.
The gameplan from both sides was simple after that, as Valencia, still needing three goals to progress, continued to press forward, while Madrid, mindful of their numerical disadvantage, adopted a defensive approach for the remainder of the game.
Di Maria was sent off with minutes to go for a petulant kick-out on Joao Pereira, but it came too late to aid Valencia, as Madrid held on for qualification, and now await a potential Clasico semi-final, should Barcelona get past Malaga on Thursday.