Wolfsburg took the lead in Kiev through Pernille Harder early in extra-time after the game had finished goalless after 90 minutes.
But after Alexandra Popp was sent off for a second bookable offence, Lyon asserted their dominance with three goals in the space of five minutes.
Amandine Henry's deflected strike got the comeback up and running, with Eugenie Le Sommer giving the French side the lead.
Goals from Ada Hegerberg and substitute Camille Abily - on her final Champions League appearance ahead of her retirement - saw Lyon secure yet another title.
It was the second time in three years the two sides had met in the Champions League final, with Lyon prevailing in 2016 on penalties.