Fiorentina set up a tie with Juventus while fierce rivals Sevilla and Real Betis will also lock horns in the next round following wins on Thursday
With Sevilla having drawn 2-2 at Maribor last week, goals from Jose Antonio Reyes and Kevin Gameiro put them in control with half an hour to play.
Although Dare Vrsic made it 4-3 on aggregate in the final minute, the Slovenian champions could not find the second that would have forced extra-time as Sevilla sealed its passage.
Sevilla will take on a Betis side which was impressive in winning 2-0 in Russia to seal a 3-1 aggregate success over Rubin Kazan.
Nono and Ruben Castro scored the goals and the upcoming derby now gives Betis a chance to salvage something from a dreadful season that currently sees the team 11 points adrift of safety at the bottom of La Liga.
Napoli coach Rafael Benitez - who won the tournament last year with Chelsea and secured progress on Thursday against Swansea - will continue his defense of the title with a tie against Porto, which sealed a dramatic away-goals victory over Eintracht Frankfurt.
After a 2-2 draw in Portugal, the Germans looked in a strong position when leading 2-0 on the night. Eliaquim Mangala leveled with a double, but the tie appeared to be settled when Alexander Meier restored Frankfurt's advantage in the 76th minute.
But with four minutes remaining, substitute Nabil Ghilas struck for the visitors to send Frankfurt crashing out.Benfica will face Tottenham in the next round after the Portuguese side ran out to a 3-0 win over PAOK to seal a 4-0 aggregate success.
Former Benfica player Kostas Katsouranis was sent off for the visitors, allowing Nicolas Gaitan to score directly from the free kick, and further goals from a Lima penalty and a fine Lazar Markovic strike secured a simple win.
Juventus and Fiorentina will meet in the next round in an all-Italian clash after Fiorentina's 1-1 draw saw it through 4-2 against Esbjerg. Lazio missed out on progression after Juninho Quixada's 88th-minute strike saw Ludogorets claim an away-goals win following a 3-3 aggregate draw.
Ludogorets will face Valencia, whose goalless draw at home to Dynamo Kiev was enough to see it through 2-0 on aggregate.
Ajax suffered its joint-heaviest European aggregate defeat, going down 3-1 to Salzburg on the night and 6-1 over the tie, while Basel's 3-0 win over Maccabi Tel Aviv saw it through after a goalless first leg to set up a meeting with the Austrians.
AZ drew 1-1 with Slovan Liberec, sealing a 2-1 win overall, and will face Anzhi Makhachkala, which beat Genk 2-0 in Belgium after a scoreless first leg thanks to a fine performance from Olexandr Aliyev.
Elsewhere, Viktoria Plzen earned a surprise 2-1 win in Ukraine to overcome Shakhtar Donetsk 3-2. Plzen's reward is a tie with Olympique Lyonnais in the next round, which beat Chornomorets 1-0 after a 0-0 draw last week.