When Arsenal travelled to Lyon for last year's semi-final, they had it all to do in France after losing the first leg 2-1.
This time they arrived with a one-goal advantage to defend.
Arsenal manager Renee Slegers said they had to "start all over again", but it was Lyon who raced out of the blocks.
Heaps was unfortunate to have a powerful header ruled out, with the referee adjudging Ingrid Engen and Ada Hegerberg to be in an offside position in front of the goalkeeper - a decision upheld after a lengthy VAR check.
But the tie turned on its head when VAR intervened again as Lotte Wubben-Moy made minimal contact with Melchie Dumornay in the Arsenal penalty area.
Although Van Domselaar saved Renard's initial effort, she went the wrong way for the retake.
Lyon continued to threaten and were rewarded when Diani poked in, while Arsenal struggled to create any clear chances in the first half.
Russo gave Arsenal a lifeline, but they failed to capitalise on a brief period of dominance and, with the game headed to extra time, VAR reared its head once more.
It took more than three minutes to check whether Brand had strayed offside, as the assistant referee had initially ruled.
But eventually there were scenes of jubilation inside the ground as replays showed Wubben-Moy had narrowly played Brand onside.
It was a disappointing end to Arsenal's European campaign, and their dreams of silverware this season now rest on the Women's Super League (WSL), although they would need to win their remaining four matches and hope leaders Manchester City slip up.