Real became the first club to win back to back Champions League titles in May 2017, then made it three in a row a year later by beating Liverpool 3-1 in Kiev.
They were among the favourites to win this year’s tournament and were on course for the quarter-finals when they beat Ajax 2-1 in Amsterdam last month, only to suffer a shock 4-1 defeat at the Santiago Bernabéu this evening.
Goals from Hakim Ziyech, David Neres and former Southampton player Dusan Tadic put Ajax 3-0 up on the night, before Marco Asensio pulled one back for the shell-shocked hosts.
However, Lasse Schöne was on hand to complete the rout just two minutes later, crowning a famous victory for Ajax, who become the first team to eliminate Real Madrid in the Champions League since Juventus in 2015.
It was the fourth straight home loss for Madrid, something that hadn't happened since 2004, and capped one of the worst weeks in the club's recent history.
It also ends an unprecedented era of dominance in the Champions League after winning three straight titles. Madrid had reached at least the semifinals in eight straight seasons and hadn't failed to make it past the last 16 since 2010.
The humiliating defeat to Ajax followed two demoralising home losses to Barcelona — 1-0 in the Spanish league and 3-0 in the semifinals of the Copa del Rey.
Ajax were playing in the last 16 for the first time since 2006 and now stand as genuine dark horses to win the tournament.
They join Tottenham Hotspur in the draw for the quarter-finals, who beat Borussia Dortmund 1-0 in Germany to complete an impressive 4-0 victory on aggregate.
After the match, Real Madrid defender Dani Carvajal said the defeat to Ajax was the worst moment of his professional career.
“I think I have never felt this awful, I do not know how to explain it,” Carvajal said after Ajax completed a 5-3 aggregate victory.
“This week everything has gone against us. Tonight we cannot look for excuses. Our opponents were better and they deserved to go through. We have to show our faces and not hide, our season has been a piece of shit.
“It's never easy to go into a game after two defeats to Barcelona, today we came here with a clear idea that we wanted to win, then two mistakes meant we were two goals down. The start of the second half was good but the third goal killed us.” Quotes from Reuters.