The 6-year-old mare prevailed by a half-length, putting a scare into her connections and much of the crowd before rallying late under Hall of Fame jockey Mike Smith.
Trainer John Shirreffs pounded his rolled up racing program against his chest after Zenyatta sailed across the finish line of the 1 1-16-mile race at her home track of Hollywood Park.
"She's a heart-stopper in so many ways," he said, smiling.
Zenyatta's exercise rider Steve Willard held his right hand over his heart, a relieved smile on his face.
"I'm sweating so much. Oh my God! It's just fabulous," said Dottie Ingordo Shirreffs, racing manager for owners Jerry and Ann Moss and Shirreffs' wife.
It was Zenyatta's final prep before she heads to Churchill Downs next month to take on the boys again in the $5 million Breeders' Cup Classic, which she won last year.
"I'm jazzed and I'm ready," Jerry Moss said about the Classic.
Zenyatta ran the distance on the synthetic Cushion Track in 1:42.97. Sent off at 1-9 odds, she paid $2.20 and $2.10. There was no show wagering because of the five-horse field.
"She has so much heart," Shirreffs said. "She digs down every time."
Switch returned $2.60. Rinterval, who lost to Zenyatta by a neck last month at Del Mar, was scratched in the paddock before the race.
The victory, worth $150,000, made Zenyatta the career earnings leader for a female horse. Her total of $6,404,580 overtook the old mark of $6,334,296 set by Ouija Board, who retired in 2006.
Zenyatta notched her eighth win at Hollywood Park, more than at any other track.
Crowds lined up five deep in spots around the paddock watching Zenyatta being saddled before the race. Female fans held up signs reading "Go Zenyatta" and "Queen Zenyatta."
She didn't disappoint, putting on her usual pre-race show by goosestepping around the paddock as the crowd cheered her and Smith. Among her high-profile fans were Penny Chenery, owner of Triple Crown winner Secretariat; actress Bo Derek; and Los Angeles Mayor Antonio Villaraigosa.
Afterward, Smith stopped Zenyatta at the top of the grandstand to check out the crowd, then guided her to the middle of the grandstand, where she bathed in a standing ovation.