Substitute Bafetimbi Gomis finished off a good move to net the only goal of the game in the 66th minute as Lyon inflicted a first group defeat on Betis and moved into first place.
However, both teams will be involved in the competition again after Christmas with third-placed Vitoria Guimaraes now unable to pip Betis to second spot after being held to a goalless draw at Rijeka.
That was the good news for Betis, but it may do little to ease the pressure on coach Pepe Mel, whose side have had an awful start to their Primera Division campaign and lie bottom of the standings with only nine points from 14 games.
They also suffered a gut-wrenching 4-0 derby mauling at the hands of arch rivals Sevilla at the weekend.
Betis have found Europe a happy distraction from their domestic woes though, and they would have guaranteed themselves a first-placed finish in Group I with a win in France.
Both sides had chances to take the lead during a goalless first half, with Lyon arguably going the closest when Alexandre Lacazette squeezed a shot past Stephan Andersen only for Betis to scramble it off the line.
Betis' best opening of the game came on the hour mark, and really should have seen them take the lead.
Samuel Umtiti's terrible attempted back-pass was intercepted by Chuli but, after nipping the ball away from Lyon goalkeeper Remy Vercoutre, he could only fire against the near post with the goal at his mercy.
That proved a costly miss as six minutes later Lyon netted the match-winning goal.
The hosts almost took the lead two minutes previously with a similar move, Andersen denying Lacazette on that occasion, but there was no denying the French side with their next opportunity.
Yoann Gourcuff's one-two with Lacazette ripped open the Betis defence and Gourcuff then rolled the ball across the area for Gomis to tap into a gaping net.
Betis pushed for a late equaliser but Markus Steinhofer saw a shot deflected wide before Chuli's stoppage-time header was tipped over by Vercoutre as Lyon held on for the win.