Lyon's quest to reach the Europa League final at their home stadium is over after CSKA Moscow eliminated Bruno Genesio's men from the round of 16 on Thursday.
The Ligue 1 side held the advantage in the tie after winning the first leg 1-0, but it was CSKA who broke the deadlock through Aleksandr Golovin in the first half at Groupama Stadium, where the tournament's decider will be staged in May.
Maxwel Cornet equalised for Lyon on the night, but two goals in the space of five minutes from Ahmed Musa and Pontus Wernbloom proved decisive.
Mariano's 71st-minute effort was not enough to save Les Gones, as the Russian Premier League club progressed on away goals following a 3-3 aggregate draw, sealing a place in Friday's quarter-final draw.
Lyon missed several good chances to take the lead, with Cornet particularly culpable, and the visitors punished that wastefulness in the 39th minute, Alan Dzagoev's well-weighted throughball releasing Golovin into space down the left.
Advancing into the area, the midfielder cut inside and curled a brilliant dipping effort over Anthony Lopes and into the top corner.
Lyon equalised in controversial circumstances in the 58th minute, Cornet turning home Jordan Ferri's cut back despite the ball appearing to have crossed the byline before the midfielder could pick out his team-mate.
CSKA responded just two minutes later, Musa slamming home from close range after running onto Kirill Nababkin's inviting delivery from the right flank.
Wernbloom then benefited from some questionable Lyon defending to connect with Konstantin Kuchaev's pass and slot home a third in the 65th minute.
Lyon refused to give up, though, Mariano leaving Igor Akinfeev no chance when he met Bertrand Traore's cross and crashed home to pull one back with 19 minutes to go.
Sustained pressure in the closing stages failed to produce the equaliser that would have sent Lyon through, as Viktor Goncharenko's side marched on, perhaps with ambitions of emulating the club's success in the 2004-05 UEFA Cup.