Sporting Lisbon sent Arsenal crashing out of the Europa League with a penalty shoot-out triumph after Pedro Goncalves's stunning equaliser, while Manchester United and Juventus eased into the quarter-finals on Thursday.
Sporting trailed when Granit Xhaka put Premier League leaders Arsenal ahead at the Emirates Stadium.
But Portugal midfielder Goncalves forced extra-time when he caught out Arsenal goalkeeper Aaron Ramsdale with a breathtaking strike from 46 yards out.
With reality television star Kim Kardashian and her Arsenal fan son Saint among the spectators, the match ended level at 1-1 on the night and 3-3 on aggregate, requiring penalties to settle the tie.
Sporting emerged with a shock 5-3 victory in the shoot-out as Gabriel Martinelli's effort was saved by Antonio Adan and Nuno Santos dispatched the winning kick.
Arsenal manager Mikel Arteta said the result was "a huge blow" and blasted his side for wasting chances.
"There were moments in the first 75 minutes where we weren't at our level. We gave every ball away and we didn't have the capacity to take the game," the Spaniard said.
"There were chances to win it in extra-time. There was a lot of uncertainty with the pens. It was a very difficult game."
It was a far calmer night for Manchester United as Marcus Rashford's swerving strike from distance earned a 1-0 win at Real Betis and a 5-1 aggregate success.
Joaquin hit the post for Betis and Juanmi spurned two clear chances for the hosts as they started well, desperately trying to overturn their three-goal deficit at the lively Benito Villamarin stadium.
However Rashford's brilliant goal early in the second half killed off the tie.
"Once you score the first goal the game is gone, and they don't have the belief anymore," said Manchester United boss Erik ten Hag.
"That is another step (forward) we made mentally, a winning attitude, to deal with that."
Three-time champions Juventus earned a 2-0 win over 10-man Freiburg to progress 3-0 on aggregate, with goals from Dusan Vlahovic and Federico Chiesa.
Juventus, leading Freiburg by a goal from the first leg, thought they had taken the lead when Vlahovic struck from close range, but it was ruled offside by VAR.
The Serbian forward then broke the deadlock just before the break from the penalty spot after Manuel Gulde handled in the box and was shown his second yellow card.
With Juventus fully in control and Freiburg at a numerical disadvantage, the tie was as good as over and Chiesa wrapped up the win late on.
Sevilla, the record six-time winners of this competition, suffered a nervy 1-0 defeat at Fenerbahce as Enner Valencia netted from the spot, but still qualified 2-1 on aggregate.
Jorge Sampaoli's Sevilla, struggling badly in La Liga, suffered defeat in Turkey but had done enough at home to progress against Fenerbahce and continue their charge.
Michy Batshuayi went off injured for the hosts early on, damaging their comeback bid, but Jorge Jesus's team took the lead when Alex Telles handled in the box.
Veteran Ecuador striker Valencia drilled home his 24th goal of the season for Fenerbahce.
Sevilla held out to progress despite pressure from the hosts in the second half, as they looked for a second goal to force extra-time.
Feyenoord thrashed Shakhtar Donetsk 7-1 on the night at De Kuip to progress to the last eight 8-2 on aggregate.
Jose Mourinho's Roma drew 0-0 at Real Sociedad to advance 2-0 on aggregate, while Bayer Leverkusen won 2-0 at Ferencvaros to clinch a 4-0 aggregate success.
In the UEFA Conference League last 16, Fiorentina thrashed Sivasspor 4-1, triumphing 5-1 on aggregate, but fellow Serie A side Lazio were knocked out, losing 2-1 at AZ Alkmaar on the night and 4-2 on aggregate.
West Ham thrashed AEK Larnaca 4-0 to complete a 6-0 aggregate stroll, with Anderlecht beating Villarreal 2-1 on aggregate after a 1-0 victory in Spain.