The Trek-Segafredo rider, who won silver in the road race at the London 2012 Olympics, sensationally broke away from the peloton with over 80km to go, in harsh, wet conditions that saw several riders crash to the floor.
"I feel so incredibly proud - women's cycling is at a turning point and today is a part of history," the 32-year-old, whose blood could be seen on her bike handlebars, said afterwards.
"I'm also proud to be part of a team making history, and even fans watching at home are making history to show there's an appetite for women's cycling - and that these athletes can do one of the hardest races in the world." - Lizzie Deignan
Deignan finished the gruelling 116km cobblestones course in 2 hours 56 minutes and 7 seconds to also become the first-ever Paris-Roubaix winner from Great Britain.
Jumbo-Visma rider Marianne Vos of the Netherlands took silver, 1min 17 seconds back, while Italy’s Elisa Longo Borghini of Trek-Segafredo finished third.
The famous race made its return after the coronavirus pandemic caused it to be postponed in 2020.
- Lizzie Deignan (GB/Trek-Segafredo) 2 hours 56 mins 7 secs
2. Marianne Vos (Ned/Jumbo-Visma) +1min 17secs
3. Elisa Longo Borghini (Ita/Trek-Segafredo) +1min 51secs
4. Lisa Brennauer (Ger/Ceratizit Pro Cycling) +2min 10secs
5. Marta Bastianllei (Ita/Ale BTC Ljubljana) Same time
6. Emma Norsgaard (Den/Movistar)
7. Franziska Koch (Ger/DSM)
8. Audrey Cordon-Ragot (Fra/Trek Segafredo)
9. Marta Cavalli (Ita/FDJ Nouvelle Aquitane Furturoscope)
10. Chantal van den Broek-Blaak (Ned/SD Worx) "