The Gunners took an early lead in the fourth minute when Alex Iwobi’s cross evaded everyone in the box and went in off the post.
It was the perfect start for Unai Emery’s men but they failed to build on it and failed to quieten a raucous crowd at Roazhon Park by sitting back.
Arsenal appeared comfortable enough but they invited the hosts back into the leg when Sokratis received a red card for two quick-fire yellows.
Benjamin Bourigeaud scored Rennes’ equaliser from the resulting free-kick after Sokratis had been sent off when he smashed a thunderous effort past Petr Cech.
The French side, who are tenth in Ligue 1, piled on the pressure after half-time and forced Emery into an early change when he replaced Iwobi with Matteo Guendouzi.
However, Emery couldn’t stem the tide of the game and Arsenal were behind just after the hour mark when a cross deflected past Cech off Nacho Monreal.
Emery appeared content with the 2-1 defeat, removing Pierre-Emerick Aubameyang and Mesut Ozil in the dying stages.
However, Rennes were not finished and Ismaïla Sarr provided the icing on the cake when he headed past Cech in the 89th minute.
Arsenal had been due to host the first leg but UEFA rulings prevented them from playing in London on the same night as rivals Chelsea.
They now must beat Rennes by two-clear goals next Thursday to stand any chance of progressing to the last-8.