Tottenham is staring elimination in the face after the last-16 first legs, while Lyon and Valencia racked up three-goal advantages.
Betis achieved an upset win over city rival Sevilla, while Fiorentina claimed a fine 1-1 draw at Juventus. Elsewhere, there were big wins for Olympique Lyonnais and Valencia but the night arguably belonged to the Portuguese duo of Porto and Benfica, which saw off Napoli and Tottenham Hotspur, respectively.
Goal takes a look at Thursday's Europa League action in pictures ...
Salzburg boss Roger Schmidt saw his side claim a 0-0 draw at Basel.
Two heavily fancied sides, Porto and Napoli, clashed at Estadio do Dragao.
Valencia took a fifth-minute lead against Ludogorets through Antonio Barragan.
Diego Alves saved Roman Bezjak's penalty for 10-man Valencia.
Valencia punished Ludogorets with another goal 33 minutes in through Fede Cartabia.
Porto took the lead against Napoli thanks to a volley from Jackson Martinez.
Arturo Vidal opened the scoring for Juventus against Fiorentina.
Real Betis took the lead against Sevilla with a Leo Baptistao header.
Gueida Fofana drags Lyon back into its clash with Viktoria Plzen.
Benfica drew first blood at White Hart Lane through Rodrigo.
AZ came away with a 1-0 win against Anzhi thanks to a Aron Johannsson penalty.
Sparks flew in as city rivals Sevilla and Betis locked horns at the Sanchez Pizjuan.
Luisao's glancing header made it 2-0 to Benfica in the 58th minute.
Pablo Osvaldo rued a missed opportunity as Juventus failed to double its lead.
Arnold Mvuemba added Lyon's third after a rapid counterattack.
Christian Eriksen offered some hope for Tottenham with a perfectly executed free kick.
Betis sealed a 2-0 away victory through the appropriately named Sevilla.
Mario Gomez earned Fiorentina a 1-1 draw in Turin with his late strike.
Luisao lashed home his second of the night to give Benfica a 3-1 first-leg advantage.
Benfica manager Jorge Jesus let Tim Sherwood know the score.