Having reached the last 16 in each of the previous two Europa League campaigns, Rangers were looking to make home advantage count against what look set to be their toughest rivals in Group A.
But Lyon – whose previous European match was a Champions League semi-final defeat to Bayern Munich in 2020 – had too much quality.
Karl Toko Ekambi's 23rd-minute stunner put Lyon ahead, with James Tavernier's own goal condemning Rangers to their first ever Europa League group stage defeat at Ibrox.
Connor Goldson could easily have been dismissed for a reckless challenge on Toko Ekambi in the 13th minute as Lyon settled quicker, though the visiting forward showed no signs of being hindered with an exceptional opener.
Having been given time to approach the area, Toko Ekambi fooled John Lundstram with some fine footwork before curling a sublime finish across Allan McGregor and into the bottom-right corner.
Joe Aribo stinging the palms of Anthony Lopes sparked the home crowd into life, and Lundstram almost atoned for his part in Lyon's opener with a low strike that flashed inches wide.
Lopes had to be at his best to keep Ryan Kent, though Islam Slimani might have put Lyon 2-0 up on the stroke of half-time had he connected with Malo Gusto's cross.
Yet Lyon struck again early in the second half. Rangers were cut open by Lucas Paqueta's pass and though Slimani's effort was blocked, the rebound bounced in off the unfortunate Tavernier.
Tavernier was inches away from dragging Rangers back into it with a superb free-kick, only for the post to come to Lyon's rescue as Gerrard's milestone match in Europe proved a disappointing one.