Real Madrid attacker Vinicius Junior was forced to hobble off injured in tears as Ajax created a nightmare first half for the Champions League title holders.
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The Brazilian missed an effort from close range, slamming his shot into the side netting in the 32nd minute, but in doing so appeared to injure his leg and was unable to continue for the beleaguered Blancos.
Marco Asensio replaced Vinicius in the 35th minute, just six minutes after another enforced substitution when Lucas Vazquez's hamstring injury led to Gareth Bale replacing him in attack.
Vinicius's performances have been one of the few bright sparks for the Madrid in recent weeks, and the club's fans will be hoping the 18-year-old's injury is not a serious one.
Ajax went into a 3-2 aggregate lead with two early goals from Hakim Ziyech and David Neres , but in truth they could have scored a couple more as Madrid's defence crumpled under intense pressure from the Dutch visitors.
Dusan Tadic's majestic turn around dumb-founded Madrid midfielder Casemiro to set up the second goal lit up social media , and Barcelona fans relished seeing future player Frenkie de Jong making light work of Luka Modric.
Santiago Solari's side looked to sorely miss captain Sergio Ramos following his booking in the first leg that suspended him for the Santiago Bernabeu return leg.
The centre-back having admitted he picked up the yellow card on purpose with Madrid holding a 2-1 lead from the Amsterdam fixture in a decision that will be ridiculed should the European champions fail to come back against eliminate the unfancied visitors.
Ramos was set to miss the first leg of the quarter-finals if Real Madrid avoided elimination against Ajax due to UEFA extending his ban by an extra game , but as it stands he will miss the first group stage game of the 2019-20 season instead.
Solari's job will also be at risk should Real Madrid lose having been defeated in back-to-back Clasicos in the past week, with a shock Champions League elimination likely to spell the end of his reign.
Madrid, managed by Julen Lopetegui at the start of the season until his sacking in October, will have little no trophies left to fight for in 2018-19 should they be knocked out by Ajax. Barcelona killed off their La Liga and Copa del Rey hopes with successive wins.
Conceding two goals to Ajax in 18 minutes marked a historic low for the Blancos, who have never conceded twice in a home matche so early in the competition before - a sharp contrast to their three Champions League final wins in a row.
