Keylor Navas and Gareth Bale were rested for the La Liga match at the Ramon Sanchez Pizjuan whilst Cristiano Ronaldo, Isco and Dani Carvajal were sidelined with respective injuries.
It meant Zidane turned to his youngsters, handing starts for Dani Ceballos, Jesus Vallejo and Theo Hernandez, but 'Los Blancos' started the match lethargically and Sevilla took full advantage.
In the 26th minute, the hosts broke the deadlock through Wissam Ben Yedder after the forward successfully beat his marker to control a flick-on from Luis Muriel, slotting under Kiko Casilla to make it 1-0.
Nacho would then be forced to hack the ball away after it went milimetres from the goal-line but it wouldn't matter as Sevilla doubled their advantage just before the break thanks to some calamitous Madrid defending.
The two centre-backs took each other out trying to stop a pass to Steven N'Zonzi in the box, leaving the midfielder free to pass to Miguel Layun who fired into the roof of the net.
However, all the action would be waiting in the second half as Madrid desperately tried to get back into the match.
They were handed a lifeline on the 57th minute when the referee pointed to the spot after Lucas Vazquez was taken out in the box.
Captain Sergio Ramos stepped up to take the spot-kick but saw his effort ricochete off the crossbar, bouncing back into play before Sevilla eventually cleared.
His day would go from bad-to-worse after his turned in a Gabriel Mercado cross into his own net to give the hosts a three-goal led with just five minutes remaining.
9 May 2018
Not content with settling for a loss though, Madrid went on a late charge and clawed a goal back through substitute Borja Mayoral in the 87th minute, heading home an inswinging cross from Marco Asensio.
'Los Blancos' would then be awarded their second penalty of the game at the death, after Mercado needlessly pushed Theo Hernandez in the box.
Despite missing his first attempt, Ramos wasn't deterred and made no mistake with the second, firing it into the bottom-right corner to make the scoreline far more respectable for Zidane's team.
Through scoring the goal, the centre-back became the first player in La Liga history to miss and score a penalty as well as conceding an own goal.
The defeat means Madrid miss out on leapfrogging their city rivals into second whilst Sevilla move into seventh, three off Villarreal with two games remaining.
9 May 2018