After three circuits around Denain, Trek Segafredo rider Deignan established a small lead over the pack just before the first of 17 cobbled sections with more than 80km remaining.
With riders struggling to organize a concerted chase, many of them slithering over on the greasy cobbles, former world champion Deignan powered into a commanding lead.
With 30km remaining the Trek-Segafredo rider held a lead of two minutes 30 seconds over a group including Vos (Jumbo Visma), team mate Audrey Cordon-Ragot and Germany’s Lisa Brennauer (Ceratizit-WNT).
Deignan, handling the bone-shaking “pave” cobblestones with aplomb, maintained her advantage as several fancied riders including European champion Ellen van Dijk crashed heavily.
Vos finally put the hammer down to try and catch Deignan, slicing into the lead as she powered through the Carrefour de L’Arbre cobbled section.
Vos closed the gap to 1:18 as Deignan began the final 10km, but Deignan proved unshakeable out front as the famed Roubaix velodrome finish approached.
Deignan was so far ahead that the finale inside the Roubaix velodrome resembled a lap of honor as the Yorkshire rider wrote her name into the cycling history books.
Vos finished more than a minute behind, with Deignan’s team mate Elisa Longo Borghini in third place.
Organizers ASO, who also own the Tour de France, added a women’s version of the 125-year-old Paris Roubaix last year, but the COVID-19 pandemic meant they had to wait another year to ride the so-called Hell of the North.
The debut for the Paris Roubaix Femmes race and for a women’s Tour de France next year are seen as steps forward in the long battle for gender equality in professional cycling, although there remains a long way to go.
While Sunday’s men’s race over a longer distance boasts a total prize pot of 91,000 euro's, the women’s race has only 7,505 euros with Deignan receiving 1,535 euro's – about 1/20th of what the winner of the men’s race will take home.