Zenyatta will break from the No. 4 post in Saturday's 1 1/4-mile race at Santa Anita.
She had also been pre-entered in Friday's $2 million Ladies' Classic, which she won last year.
But owners Jerry and Ann Moss, along with trainer John Shirreffs, had a bigger goal in mind for the 5-year-old mare, who has won all four of her starts this year.
"There's an opportunity to make history in the Classic, that's why we chose the Classic," Shirreffs said on Tuesday, referring to the fact that no female horse has ever won in the race's 25-year history.
Zenyatta will be just the fourth female to run in the Classic. Jolypha had the best result, finishing third in 1992. Azeri was fourth in 2004 and Triptych was sixth in 1986.
"I believe she deserves this chance," said Hall of Fame jockey Mike Smith, who rides Zenyatta. "If she gets her opportunity to run her race and she runs it like I know she can, we might see something pretty incredible."
With a victory, Zenyatta would better Personal Ensign's career mark of 13-0 set from 1986-88. That filly retired as the first undefeated champion in American racing in more than 80 years.
"I hope it gets more people interested," Jerry Moss said. "I hope it gets more people watching. I hope they get to appreciate Zenyatta for what she is - a great, unique, special equine athlete."
Missing from America's richest race is Preakness Stakes winner Rachel Alexandra, the 3-year-old filly who won all eight of her races this year, including three victories over male competition.
Her owner, Jess Jackson, shut her down for the year because he doesn't like Santa Anita's synthetic surface, where his two-time U.S. Horse of the Year Curlin faded to fourth in last year's Classic.
Zenyatta has won 11 races on synthetic surfaces, including three at Santa Anita. Her lone win on traditional dirt came in Arkansas.
She will take on a loaded field that includes Ireland-bred Rip Van Winkle, the bettors' second choice, and Summer Bird, the third choice who swept the Belmont Stakes, Travers and Jockey Club Gold Cup but will test himself on synthetics for the first time.
Rip Van Winkle will try to give Europe a second straight win in the Classic, where Raven's Pass triumphed last year and European horse Henrythenavigator finished second.
Mine That Bird, winless in four races since his stunning upset in the Kentucky Derby, was listed at 12-1, along with six other horses.
Trainer Chip Woolley Jr. shrugged off Mine That Bird's long shot status, saying, "He won the Derby at 50-1."
Trainer Bob Baffert, who will saddle Pacific Classic winner Richard's Kid, saluted the Mosses for giving Zenyatta a shot at the boys.
"That's pretty gutsy," he said. "That's what our sport needs. We need a big boost right now and she's going to be our boost. Rachel (Alexandra) carried us to a certain point and this mare is going to the rest of the way."
The 14 races to be run on Friday and Saturday for the second consecutive year at Santa Anita are worth $25.5 million. A total of 149 horses were entered, including 30 from Europe.
Without Zenyatta, the Ladies' Classic attracted a field of eight, led by early favorite Music Note.
Ireland-bred Goldikova is back to defend her title in the Mile on the turf as the early favorite. Two other Ireland-breds are favorites in their races. Mastercraftsman is the choice in the Dirt Mile, while Conduit is listed tops in the Turf.
