Hapoel Kiryat Shmona were left heartbroken after a stoppage time winner from Lyon denied them a point following an heroic comeback.
The Israeli champions made a rip-roaring start with Shimon Abuhazira putting them in front after seven minutes.
But Lyon hit back with three goals in 14 minutes from Gueïda Fofana, Fabian Monzon and Anthony Reveilliere to turn the game on its head at the Kiryat Eliezer.
A 51st strike from Lior Levi hauled Hapoel back into the match and completed the rousing comeback when Abuhazira held his nerve to convert from the penalty spot, only for Fofana’s last-gasp header from a Steed Malbranque's corner to snatch victory for the Ligue 1 club who finished the night top of Group I on six points.
Hapoel boss Barak Bachar said: "We were close to recording an amazing result. I’m very proud of the players."
Elsewhere, an injury time striker from Omer Damari earned Hapoel Tel Aviv their first point of the group stages as they drew 1-1 with Academica.
After a goalless first half, Salim Cissé put Academica ahead two minutes into the second period.
Hapoel dominated the remainder of the half and Damari converted a precision cross from Gil Vermouth to earn the Israelis a point in their first match under new manager Yossi Abuksis.
He said: "We're happy we managed to equalise and bring away an important point for the long haul in this group.
"We didn't give up on the game even at the very end, and this shows we have character. I'm happy the substitutes changed the game."
1. Athletico Madrid Pl. 2, Pts. 6
2. Viktoria Plezen Pl. 2, Pts. 3
3. Academica Pl. 2, Pts. 1
4. Hapoel Tel Aviv Pl. 2, Pts. 1
1. Lyon Pl. 2, Pts. 6
2. Sparta Praha Pl. 2, Pts. 4
3. Hapoel Kiryat Shmona Pl. 2, Pts. 1
4. Athletic Pl. 2, Pts. 1