Arsenal took an early lead against Rennes on Thursday night, but a red card for Sokratis Papastathopoulos changed the game as the Gunners slumped to a 3-1 defeat.
Villarreal and Dinamo Zagreb also won and the other two early games, Sevilla v Slavia Prague and Eintracht Frankfurt v Inter Milan, ended all square.
Arsenal had never lost to French opposition away from home in 12 previous European games and they took an early lead when what looked like a cross from Alex Iwobi evaded everyone and sneaked in at the far post.
Playing in their change turquoise-green shirts, the English side looked to be in control but the match changed completely four minutes before halftime when Papastathopoulos was sent off for a second bookable offence.
Rennes equalised from the resulting free-kick when Benjamin Bourigeaud rifled home at the second attempt and they came out for the second half looking far more positive than the London side.
The French side went ahead 20 minutes into the second half when Mehdi Zeffane’s shot looped off defender Nacho Monreal into the net and Ismaila Sarr made it 3-1 two minutes from time when he powered home a header from a lovely curling left-wing cross.
Sevilla, who have won the Europa League three times, twice went ahead against Slavia Prague but were pegged back on both occasions in a pulsating 2-2 draw in Spain.
Wissam Ben Yedder put the home side ahead in the first minute and although Miroslav Stoch equalised with a deflected shot, Munir restored Sevilla’s lead.
Alex Kral put the visitors level again six minutes before halftime when he turned a corner into the net.
Fellow Spaniards Villarreal had a happier evening in St Petersburg and will take a solid 3-1 lead into the second leg at home.
Villarreal, third bottom of La Liga, went ahead against Zenit after 33 minutes when Vicente Iborra headed home from a free kick but the home side took only two minutes to level thanks to Sardar Azmoun, whose quick thinking allowed him to stab home from close range.
The Spaniards, though, took control in the second half, with Gerard Moreno putting them 2-1 ahead after 64 minutes and Manu Morlanes added the third.
Bruno Petkovic scored a penalty for Dinamo Zagreb to give them a 1-0 home win over Benfica while in the only game between two former winners of the UEFA Cup, Eintracht Frankfurt was held 0-0 at home by Inter Milan.
It was the first time Eintracht, who have won seven of their eight Europa League matches this season, failed to score.