The Mitchelton–Scott leader chased van der Breggen (Boels-Dolmans) for 15km after being dropped in the final push to the top of the Col de la Colombière.
She produced the unlikeliest of comebacks in the finale, overcoming van der Breggen with 20 metres left in the race to take a memorable win. Ashleigh Moolman-Pasio (Cervélo–Bigla) came in third.
"Last year was nice, but this was a race," said van Vleuten. "With 200 metres to go I thought I got second, but then I saw her dying. To win like this... I know I'm in good shape but Anna van der Breggen is also a really good cyclist. It was a really tough ride, but beautiful."
"I could have given up with 500 metres to go, but I kept going. Always that everything is possible. This one was really beautiful. Together with the Giro Rosa last week and this one.. it is really high on my wishlist."
Four climbs characterised the 118km course from Lake Annecy through the French Alps, close to the Swiss border and the first splits started to show on the first of these, the Col de Bluffy.
Over the top of the next climb, the Cote de Saint-Jean-de-Sixt and four riders broke clear with a couple of chasers in between and gained over two minutes on the peloton with 50km left to race. Included in the break were Lotta Lepisto (Cervelo-Bigla), Leah Kirchmann (Team Sunweb), Malgorzata Jasinska (Movistar) and Leah Thomas (UHC).
As the field sped along the valley floor towards the final climbs of the Col de Romme and the iconic Col de la Colombiere the gap started to reduce and on the early slopes of the Romme the favourites group formed and only two riders remained out front.
Cecile Uttrup Ludwig (Cervelo-Bigla) used early pressure to launch her attack, with the young rider launching of the front of the main group and powering her way up the climb.
Australian Amanda Spratt and Van Vleuten were side-by-side in that main group as they started the Colombiere with Ludwig around a minute ahead, attack after attack thinned out the group inside the closing 20kilometres and Van Vleuten was part of a strong trio chasing down Ludwig towards the summit.
Van der Breggen and Asheligh Moolman (Cervelo-Bigla) followed every move of Van Vleuten and the trio passed Ludwig before the summit. Van der Breggen attacked immediately and gained a slight advantage going into the descent towards the finish.
Van Vleuten went in pursuit on the downhill, not gaining much time, but managed to catch van der Breggen on the rise before the line to take the victory by a single second.