In addition, Big Brown became the second winner to start from the No. 20 post. The gelding Clyde Van Dusen did it in 1929.
Big Brown covered the 1 1/4 miles in 2:01.82 in front of the second-largest crowd in Derby history. He paid $6.80, $5 and $4.80.
Eight Belles paid $10.60 and $6.40, and Denis of Cork, at odds of 27-1, returned $11.60.
Dr. Larry Bramlage, the Derby's on-call veterinarian, said the filly's injuries were too severe to even attempt to move her off the track.
"She didn't have a front leg to stand on to be splinted and hauled off in the ambulance, so she was euthanized," Bramlage said.
Trainer Larry Jones paid tribute to his fallen filly saying, "She ran the race of her life."
And he defended having her run against 19 colts in the Derby.
"It wasn't that. It wasn't the distance. It wasn't a big bumping match for her. She never got touched," he said. "She passed all those questions ... with flying colors. The race was over, all we had to do was pull up, come back and be happy. It just didn't happen."
Tale of Ekati was fourth, followed by Recapturetheglory, Colonel John, Anak Nakal, Pyro, Cowboy Cal, Z Fortune, Smooth Air, Visionaire, Court Vision, Z Humor, Cool Coal Man, Bob Black Jack, Gayego, Big Truck, Adriano and Monba.
The colt earned $1,451,800 for the win and boosted his earnings to $2,114,500 for owners IEAH Stables and Paul Pompa Jr. Pompa, who named Big Brown in honor of United Parcel Service, a client of his trucking business, sold a 75 percent interest in the colt to IEAH for about $3 million after his first race.
Desormeaux won the Derby for the third time, having won aboard Real Quiet in 1998 and Fusaichi Pegasus in 2000. Only three other riders have won more — Eddie Arcaro, Bill Hartack and Bill Shoemaker.
"It was smooth sailing all the way," Desormeaux said. "The horse was very comfortable."
Big Brown was the third favorite to win in the past five years. Smarty Jones won in 2004 and Street Sense won last year.
All eyes were on Big Brown at the start. Dutrow called his colt the fastest of all and he proved it when Desormeaux gunned him close the lead on the mad dash to the first turn. Desormeaux did a masterful job of keeping Big Brown free and clear of any traffic issues.
As the field headed into the backstretch, Big Brown was in sixth place and waiting for Desormeaux's signal to make his move. It came around the far turn, and Big Brown took the lead at the top of the stretch and was never challenged to the wire.
"I don't even know what we just did," Dutrow said. "I can't express my feelings, only that it was one of the most incredible feelings I ever had, and I can't wait to feel it again."