The hosts were faced with a near impossible task of overturning a huge deficit from the first leg, but produced a positive start as Maximilian Wober tested Ryan.
Valencia, though, responded and broke the deadlock on the hour as Rodrigo chipped the goalkeeper before Sofiane Feghouli latched onto a throughball from Danilo to make it 2-0 after 64 minutes.
Pablo Piatti added a third on 73 minutes, scoring from Feghouli's pass into the penalty area, before defender Ruben Vezo headed in a late fourth.
Ryan's Australia team-mate Robbie Kruse was also in action, coming off the bench in the 88th minute as Karim Bellarabi scored twice as Bayer Leverkusen beat Sporting 3-1 at the BayArena.
The German side were defending a 1-0 advantage from the first leg, and were in command after half-an-hour when winger Bellarabi netted his second goal of the tie.
Joao Mario (38) pulled one back for the Portugese side, but Bellarabi (65) cracked in another before Hakan Calhanoglu (87) struck a late volley.
Fenerbahce drew 1-1 at Lokomotiv Moscow, as they progressed through 3-1 on aggregate.
After Alan Kasaev had seen a goal incorrectly ruled out for offside, Aleksandr Samedov (45) gave the Railwaymen hope after netting a close-range effort just before half-time.
However, the Turkish side held out and Mehmet Topal (83) settled matters late on with a looping header from a near-post corner.
Miroslav Klose finally scored his first goal of the season as Lazio dumped Galatasaray out with a 3-1 home win to progress 4-2 on aggregate.
Marco Parolo headed the Italian side in front (59) before Felipe Anderson (61) quickly doubled the advantage.
Yasin Oztekin (63) immediately reduced the arrears, but Klose (72) made sure of safe progress when he tapped in Stefan Radu's centre from six yards.
Sparta Prague are also through after beating Krasnodar 3-0 away.
Sparta, leading 1-0 from the first leg, went ahead early in the second half through Lukas Marecek (51) before Martin Frydek's (57) header doubled the lead.
After midfielder Charles Kabore was sent off for a second yellow card, Kehinde Fatai (70) fired in a third.
A late goal from substitute Sabin Merino sent Athletic Bilbao into the last 16 with a hard-fought 2-1 aggregate victory over Marseille.
The Spanish side had won 1-0 at the Stade Velodrome, but Michy Batshuayi levelled the tie just before half-time.
However, Merino's header with just nine minutes left proved enough to send Bilbao through.
Shakhtar Donetsk won 3-0 at Schalke.
The tie was goalless after the first leg in Lviv, and after Schalke hit the post through Johannes Geis's free-kick, the visitors went ahead on 27 minutes through a clever backheel from Marlos.
Facundo Ferreyra (63) tapped in a second, before Viktor Kovalenko's (77) powerful drive gave the Ukrainian side a third.
