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 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 verge of Europa League elimination.
The French side fielded Samuel Umtiti for his first start of the season at left-back while also resting Bafetimbi Gomis. On the other hand, Marcelo Bielsa preferred Aritz Aduriz to Fernando Llorente up front in a surprisingly slow start in the Rhone Valley.
Neither side could truly assert their authority in the opening stages of the encounter, as Lyon were denied a decent opportunity by the offside flag. Nevertheless, the first chance of the game fell to Steed Malbranque, who saw an effort fly wide of the target.
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 parried the ball away to safety.
Then, a poor Anthony Reveillere back-pass was cut out by Aduriz, with Dejan 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 sluggish, though signs of an imminent goal were growing as De Marcos charged down the wing but once more opted to test Vercoutre, rather than squaring for his 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 flank. Vercoutre inexplicably rushed out to meet the defender, who lobbed the goalkeeper before clipping the bar. Aduriz surprisingly wasted the rebound with a poor finish.
The striker 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 soon rewarded. A lofted ball from Iraola was helped on by the powerful Llorente, and substitute Ibai Gomez struck an exquisite half-volley into the net to delight the travelling support.
Lyon stepped up their plans to retake the lead and only a world-class stop by Iraizoz could stop Gomis from achieving that. The dreadlocked forward let fly with a dipping effort from range, but the glovesman repeated the trick once more to deny the substitute.
The frantic end to the match continued as Susaeta latched onto Llorente's pass, but saw 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 pool.
Les Gones 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.