Enable has become the first Prix de l'Arc de Triomphe winner to follow up with success at a Breeders' Cup fixture.
Ridden by Frankie Dettori and racing for only the third time this season because of injury, the four-year-old saw off Irish challenger Magical in the Breeders' Cup Turf race at Churchill Downs in Louisville, Kentucky.
Trained by John Gosden for owner/breeder prince Khalid Abdullah, the double Arc winner won by less than a length with Sadlers' Joy third.
Eight previous winners of the Arc, including Dancing Brave (1986) and Gosden's Golden Horn, also ridden by Dettori (2015), have been defeated in races at the Breeders Cup when lining up in the same season.
Earlier, another brilliant Dettori ride saw Expert Eye produce a perfectly-timed run to win the Breeders' Cup Mile.
It was a first success in the prestigious Mile race for 10-time champion trainer Sir Michael Stoute.
The colt, wearing the colours of Abdullah, was off the pace early on and still had plenty to do in the straight
But he produced a devastating turn of foot to chase down Catapult and Analyze It in the final strides.
"Frankie was great on him," said Stoute. "He scared me a bit, but he was brilliant on him, he knew what was under him. He just got there in time."
BBC racing correspondent Cornelius Lysaght
What Enable and the John Gosden team have achieved is astonishing really; the horse's season has been ravaged by setbacks and didn't even get going until September but, despite the challenging preparation, she's still made history.
Looking at some of those eight who've failed - Dancing Brave et al - tells its own story. But, of course, maybe the freshness after just three runs was actually the key.
She was always going well through the race. After striking for home - quite wide - another talented filly, Magical, threw down the mightiest of gauntlets, but Enable saw her off magnificently.