Dual American champion Wise Dan has been ruled out of a tilt at a third Breeders' Cup Mile victory at Santa Anita with an ankle injury.

Owner Morton Fink said the injury to Wise Dan's right front fetlock most likely happened during his win in the Shadwell Turf Mile at Keeneland on October 4.

Fink said trainer Charlie LoPresti checked Wise Dan ahead of a scheduled gallop this week and noticed swelling in the horse's ankle. The fracture was confirmed in an X-ray.

"This is not a fracture that can be helped with surgery. He has to heal it on his own," Fink said in a statement.

"We won't decide if he will return to training until we see if he heals perfectly because he has nothing left to prove.

"Wise Dan has accomplished a lot in his career so far, and given us endless joy. We would never want to race him unless he is 100 per cent."

Wise Dan is unbeaten in four starts this year after his season was interrupted by colic surgery. He won two Group One races in April and May before the emergency surgery.

Wise Dan has 23 wins from 31 starts, including 11 at the top level.