Everton were beaten 3-0 in Lyon on Thursday evening, a result which now means the Toffees cannot qualify for the Europa League’s knockout phase.
Bertrand Traore, who netted the winner on Merseyside a fortnight ago, scored another important goal in this meeting in south-east France.
Traore rounded Pickford midway through the second half to put Lyon in front, before substitute Houssem Aouar doubled the home side’s advantage with 14 minutes remaining.
To rub salt into the wounds, Morgan Schneiderlin was then sent off for a second bookable offence and Memphis Depay headed in a third to seal the result.
The defeat, coupled, with Atalanta’s 1-1 draw at Apollon Limassol, means Everton can now no longer finish in Group E’s top two positions.
David Unsworth made six amendments to the side that played at Leicester City, the most noteworthy inclusion being that of Beni Baningime, who made his first Europa League appearance for the Club. Ademola Lookman and Gylfi Sigurdsson came into the Blues’ forward line in the absence of Wayne Rooney who, along with Phil Jagielka and Leighton Baines, hadn’t made the journey across the Channel.
Everton, kitted out in the navy and purple third strip, were greeted by a vociferous, partisan home support. The 60,000-capacity Groupama Stadium wasn’t full but there was still plenty of noise emitted by home fans at both ends of the stadium. The travelling Blues contingent, nearly 3,000 located high in the upper tier, also did their bit to create a lively atmosphere.
Lyon started on the front foot and Cuco Martina, deployed at left-back, received an early booking for tugging on the shirt of Maxwel Cornet to halt a swift and potentially dangerous break down the hosts’ right.
The Ligue 1 outfit saw plenty of the ball early on but encountered a three-man shield of Schneiderlin, Gana and Baningime sitting in front of the Blues’ defence.
Jordan Pickford’s first contribution midway through the first half was to beat away a header from Traore. It was a save made even better seconds later as he quickly regained his footing to get a telling touch on Ferland Mendy’s threatening low cross through the six-yard box from the recycled play.
Playmaker Nabil Fekir saw an effort fly over the bar and there was a heart-in-mouth moment when Mason Holgate sliced a clearance, only for it to be clutched by the vigilant Pickford.
Lyon continued to attack and the Everton keeper was then forced to push away a free-kick from former Manchester United forward Depay, which was fiercely-struck from all of 35 yards.
It was a faultless first-half performance from Pickford, as he later denied Traore for a second time in the contest.
The game was still locked scoreless at the break - but there had been a worrying incident in the lead-up to half-time. Martina landed awkwardly following an aerial challenge and left the pitch on a stretcher after extensive medical treatment. Muhamed Besic was his replacement and it culminated in seven minutes of stoppage time.
Having gone the opening 51 minutes without seriously troubling Anthony Lopes, Gana brought the Lyon glovesman into the action seconds after the restart. Aaron Lennon crossed from the left and, with a sight of goal opening up, Gana didn’t quite get enough power on his shot and Lopes got down to make a necessary intervention.
On 55 minutes, the home fans cried for a penalty when Fekir went to ground inside the area under a challenge from Holgate. Instead, Israeli referred Orel Grinfeld gave the decision the other way, deeming the Lyon playmaker had taken a tumble too easily and then handled the ball.
With a third of the contest left, Unsworth went more attacking, switching Gana for Dominic Calvert-Lewin, which subsequently allowed Sigurdsson, who had led the line up to that point, to play slightly deeper.
Within minutes of the change, the Icelander flashed a left-footed shot narrowly past the post.
Everton were then hit by the sucker-punch as the ball fortuitously broke for Traore, who rounded the advancing Pickford and slid the ball into the net to give Lyon the advantage as the second half reached its mid-point.
Lyon then doubled their lead as the ball was worked from right to left and Aouar slid the ball into corner of the net.
And it got worse for Everton when Schneiderlin was given his marching orders after picking up his second yellow card of the contest with 10 minutes remaining.
Depay added a final blow and wrapped up all three points for Bruno Génésio’s side in the dying minutes with a well-placed header into the bottom corner.
Next up for Unsworth and his men is a return to Premier League action with the visit of Watford to Goodison Park on Sunday.