The three-year-old bay colt was the first horse in 37 years to sweep the Triple Crown of the Kentucky Derby, Preakness and Belmont Stakes and has captured the imagination of the American public with his performances.
Despite a rare defeat in August at Saratoga, American Pharoah started an odds-on favorite Saturday for the $5 million race and never looked like losing.
Breaking from the stalls quickly, jockey Victor Espinoza took the wonder horse into an early lead, which he never relinquished.
The eventual margin of victory was six and a half lengths from Effinex, with Honor Code third.
It sparked a frenzy at Keeneland with trainer Bob Baffert paying an emotional tribute.
"I wanted him to go out the champion that he is," he said.
American Pharoah will go to a lucrative stud career with a record on nine wins from 11 starts, losing his first race and his penultimate appearance, but so dominant in the others.
He has earned his connections the small matter of $8,650,300.
Golden Horn beaten
Earlier, Prix de l'Arc de Triomphe winner Golden Horn suffered a narrow defeat in the Breeders' Cup Turf in his farewell race.
The filly Found, ridden by Ryan Moore, pipped Frankie Dettori, on board Golden Horn, up the stretch in the $3 million race.
Golden Horn had also won the Epsom Derby and the Eclipse Stakes as well as Europe's most prestigious race, earning a reputation on the other side of the Atlantic to match American Pharoah.
There had been speculation the two might meet in the finale to their careers, but connections of Golden Horn did not want him to race on the dirt surface which was used for the Breeders' Cup Classic.