Lyon's Amandine Henry, Eugenie Le Sommer, Ada Hegerberg and Camille Abily got on the scoresheet after Pernille Harder's deflected strike had put the German side ahead early in the extra period after the game finished goalless in 90 minutes.
Lyon, seeking a third straight Champions League triumph and a fifth overall to eclipse four-times winners FFC Frankfurt, dominated possession and had more chances but were stifled by a resolute Wolfsburg defence and goalkeeper Almuth Schult.
The German champions looked as if they were still recovering from being taken to extra time and penalties in Saturday's German Cup final when they beat Bayern Munich.
Eugenie Le Sommer and Ada Hegerberg of Lyon celebrate with the trophy during the UEFA Womens Champions League Final between VfL Wolfsburg and Olympique Lyonnais on May 24, 2018 in Kiev, Ukraine.
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However, Wolfsburg did take the lead when a long throw out by Schult reached Harder who strode into the opposition half and shot from 25 metres. The ball clipped the heel of Lyon captain Wendie Renard and trickled past goalkeeper Sarah Bouhaddi.
The German side's joy was short-lived when midfielder Alexandra Popp flew in with a reckless challenge and received a second booking, reducing Wolfsburg to 10 players.
It proved to be costly, as Lyon equalised two minutes later. Defender Lena Goessling failed to clear and Henry capitalised, taking the ball into the area and firing into the top corner.
The French side took the lead almost straight from the restart when substitute Shanice van de Sanden raced down the right and into the box, putting in a low cross for Le Sommer to flick the ball into the net.
Lyon celebrate their win
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A scuffed half-volley from Hegerberg shortly before halftime in the extra period made it 3-1 and meant the Norwegian became the first player to score 15 goals in a Champions League campaign.
Veteran Abily, who will retire at the end of the season, fittingly sealed the win with a clean strike four minutes from the end.
The Frenchwoman has played a part in each of Lyon's victorious European campaigns and can cap her career with a glittering treble when the league champions take on Paris St Germain in the French Cup next week. (Reporting by Christian Radnedge; Editing by Ken Ferris)