While English clubs were toiling, Spain's four representatives all recorded victories with Gary Neville's Valencia hitting Rapid Vienna for six.
Neville had a 41st birthday to remember as Valencia became the first team to score five goals in the first half of a Europa League game - Santi Mina (2), Daniel Parejo, Alvaro Negredo and Andre Gomes all on the scoresheet.
Valencia eased off in the second half but substitute Rodrigo rounded off a 6-0 win, which equalled Steaua Bucharest's record victory in the competition, set 18 months ago.
Reigning champions Sevilla thrashed Molde 3-0 to almost certainly book their place in the last 16.
Fernando Llorente struck twice and Kevin Gameiro added a third as Ole Gunnar Solskjaer's men were blown away.
Fellow Spaniards Villarreal will also defend a first-leg lead after beating Serie A side Napoli 1-0 at El Madrigal.
Denis Suarez - who helped Sevilla win the Europa League last season - came up with the decisive moment when his dipping free-kick beat goalkeeper Pepe Reina via the underside of the crossbar.
And Athletic Bilbao were also 1-0 winners at Marseille with Aritz Aduriz's spectacular 35-yard volley, his 26th goal of the season, splitting the sides.
Galatasaray and Lazio fought out a 1-1 draw - Sabri Sarioglu's early finish cancelled out by Sergej Milinkovic-Savic - and Shakhtar Donetsk and Schalke are also level after a goalless draw in Ukraine.
Goals from Lukasz Piszczek and Marco Reus handed Borussia Dortmund a 2-0 victory over Porto.
Piszczek put Dortmund on the way to a comfortable victory after just six minutes at Signal Iduna Park and Reus made it two 19 minutes from time to leave Porto with an uphill task in Portugal next week.
Bayer Leverkusen beat 10-man Sporting Lisbon 1-0 away with Karim Bellarabi grabbing the all-important goal after 26 minutes.
Sporting will be without defender Ruben Semedo in next week's second leg in Germany after the defender was sent off for a second bookable offence after 74 minutes.
Fellow Portuguese side Braga had a better night with a 2-1 win against Sion in Switzerland, Nikola Stoiljkovic and Rafa Silva on target for the visitors with Moussa Konate replying.
St Etienne beat Basle 3-2 in an entertaining contest at the Stade Geoffroy-Guichard with substitute Jean-Christophe Bahebeck the hero.
Moustapha Sall and Kevin Monnet-Paquet scored to put Les Verts in cruise control, but Basle were level by the hour mark through Walter Samuel and a Marc Janko penalty.
But Bahebeck had the final word after 77 minutes to give St Etienne a narrow advantage in Switzerland next week.
Anderlecht beat Olympiacos 1-0 at home with Kara Mbodji's controversial 67th-minute effort allowed after a lengthy discussion between referee and linesman, with the Greeks complaining of a foul on goalkeeper Roberto.
Lukas Julis' second-half header gave Sparta Prague a slim 1-0 advantage over Krasnodar.