After a successful season in which she went undefeated, Zenyatta was awarded the Eclipse Award for being the top older female of 2008, and was voted as the runner-up for the American Horse of the Year award.
On May 23, 2009, Zenyatta began another season of racing with the Milady Handicap, a race she had entered the previous year, at Hollywood Park. Because she was fast, she carried 126 pounds. She and a horse from her own stable, Life is Sweet, battled down the homestretch, with Zenyatta coming first by 1 3/4 lengths. Next, she entered the Vanity Handicap on June 27. Despite her burden of 129 pounds, over ten pounds more than her opponents, Zenyatta came first by 2 1/2 lengths.
After her two handicap races, Zenyatta moved on to race in a stakes race, the Clement L. Hirsch Stakes, on August 9. With just a furlong left, she was four lengths behind the first place horse, Anabaa's Creation. She used one last burst of energy to catch up with the other horse, winning by only head.
Next, she entered the Lady's Secret Stakes for the second yeard in a row, on October 10. After she defeated every other horse on the track, her trainer decided to enter the horse in the Breeders' Cup Classic on November 7. She would be racing against many champion racehorses. During the race, Zenyatta galloped down the racetrack, defeating champions such as 2009 Kentucky Derby winner Mine That Bird, Rip van Winkle, 2009 Belmont Stakes winner Summer Bird, and Champion Older Male Gio Ponti. She came in first place over Gio Ponti by a length, making her the first female to win the Breeders' Cup Classic.
At the beginning of 2010, she was awarded the Eclipse Award for top Older Female of 2009 and was runner-up to Rachel Alexandra for Horse of the Year honor. Though everyone was told that she would be retiring, Zenyatta continued her career through the season of 2010, beginning with a victory at the Santa Margarita Invitational at Santa Anita on March 13. She had weaved through the pack of horses, passing them mid-way through the homestretch.
Next, on April 9, she entered the Apple Blossom Invitational, where it was planned she would race against the champion Rachel Alexandra. However, Alexandra didn't enter because of a recent loss, and Zenyatta went on to defeat the other horses.
On June 13, Zenyatta won her 17th consecutive race, the Vanity Handicap, with 129 pounds on her back, breaking both Cigar's and Citation's records of consecutive races won. Next, she won the Clement L. Hirsch Stakes on August 7 and the Lady's Secret Stakes on October 2. At that point, she had gone undefeated in all her nineteen races. However, that ended when she entered the Breeders' Cup Classic on November 6. She fell far behind the leader, Blame, demonstrating the Thoroughbred heart when she ran her fastest to catch up, losing only by a head.
That year, she once again earned the Eclipse Award for top Older Female, also earning the Horse of the Year award for 2010 and the Secretariat Vox Populi Award. She also is noted as the first female to win the Vanity Handicap, the Clement L. Hirsch Stakes, and the Lady's Secret Stakes for three years in a row. She is considered one of the greatest female racehorses.