Remi Garde's men struck late on to deny Marcelo Bielsa's side - who had equalised through Ibai - a well earned draw in a frantic finish at the Stade Gerland
Lisandro Lopez opened the scoring midway through the second half, before Ibai Gomez cancelled it out with a sumptous half-volley from distance after sustained pressure from the visitors.
Despite a frantic effort, Les Gones would reclaim their advantage as Jimmy Briand tapped into an empty net to leave Athletic on the edge of Europa League elimination.
The French side fielded Samuel Umtiti for his first start of the season at left-back, whilst also resting Bafetimbi Gomis with Marcelo Bielsa preferring Aritz Aduriz to Fernando Llorente up front in a surprisingly slow start in the Rhone Valley.
Neither side could exactly assert their authority in the opening stages of the Group I encounter, as Lyon were denied a decent opportunity by the offside flag. Nevertheless, the first chance of the game fell to Steed Malbranque, who opted for goal, rather than a continuation of a move - instead seeing his effort fly wide of goal.
At the other end, Athletic were penetrating, and their progress was curtailed by a fine Remy Vercoutre save. Aduriz found space in the box to fire a considerably acute shot at the goalkeeper, who was equal to it, parrying away to safety.
Remi Garde's men were far more solid at the back than in their previous Europa League encounter - a nervy 4-3 win over Israeli outfit Hapoel Ironi Kiryat Shmona, and the hosts were looking to quash any threat - despite Oscar De Marcos causing slight alarm with a fine touch yards in front of Dejan Lovren, before Bakary Kone's intervention.
The Croatia international redeemed himself seconds later, as a poor Anthony Reveillere back-pass was cut out by Aduriz, with Lovren producing a brilliant sliding tackle to thwart the visitors once more before Malbranque further tested Gorka Iraizoz with a stinging low effort.
The second half was equally slow in tempo, though signs of an imminent goal were growing as De Marcos raced through on the wing, but once more opted to test Vercoutre, rather than once more, squaring for waiting team-mates.
Nevertheless, a goal did arrive soon after. Reveillere delivered in an angled cross on the right-wing, which was met powerfully by Lisandro Lopez, who headed past Iraizoz and into the net for his 25th European goal on 54 minutes.
Los Leones were denied by the woodwork two minutes later, as a fine Iker Muniain pass opened up Andoni Iraola on the wing. Vercoutre inexplicably rushed out to meet the defender, who lobbed the goalkeeper before clipping the bar, as Aduriz surprisingly wasted the rebound with a poor finish.
Marcelo Bielsa's men were once more denied as Ander Iturraspe's weighted pass into a on-side Markel Susaeta failed to take advantage of some sloppy play by the Lyon goalkeeper.
Aduriz was sacrificed for Llorente midway through the second half, as Bilbao searched for the equaliser, but they were close to falling further behind as substitute Gomis held off Iturraspe before firing inches wide.
Despite sustained pressure, the visitors were rewarded finally. A speculative lofted ball from Iraola was helped on by the powerful Llorente, as substitute Ibai Gomez struck an exquisite half-volley into the net, and send the travelling support into delirium.
Lyon pressure to regain their advantage, and only a world-class stop by Iraizoz would stop Gomis from achieving that, after the dreadlocked forward let fly with a dipping effort from range, before the goalkeeper repeated the trick once more to prevent the substitute.
The frantic end to the match continued as Susaeta latched onto Llorente's pass, before seeing his goal-bound effort tipped over by Vercoutre, as Lyon hit on the counter with five minutes to go.
The winner came as Gomis' effort was parried into the path of Briand, who would be afforded an easy tap-in to condemn last season's runners-up to a second defeat in the group.
Lyon top Group I with a 100 per cent record, eight points ahead of the Basque outfit, who will now be seeking revenge at San Mames in two weeks' time.