Guarnier ended up finishing fourth, 1:28 behind Van Vleuten, with Italy's Elisa Longo Borghini taking third place for Wiggle-Honda.
The race ends on Saturday with a 22.5km "chase" in Marseille.
"Megan put her hand up at the start of the day and said she could be leader".
The member of the Australian Orica-Scott team finished 40 seconds clear of top British rider Lizzie Deignan.
"I wouldn't call myself a time triallist but perhaps this gives me a chance [for overall victory]".
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Boels-Dolmans' Deignan began the day saying she was exclusively here as a domestique to support her team-mate Megan Guarnier in the Tour de France's women's event, but once it became clear the American did not have the legs Deignan fought for victory herself.
The 34-year-old Van Vleuten suffered a horror crash in the Olympic road race last year, but said her performance in Rio had convinced her she could contend on a mountainous course.
She has been in impressive form this season, winning two stages of the Giro Rosa stage race and leading the women's World Tour standings.
"To finish here in front of so many people is incredible", she said.