Animal Kingdom produced a strong late charge to clinch victory by more than a length in the 137th Kentucky Derby.
Trained by English-born Graham Motion and ridden by John Velazquez, it was his first appearance on a dirt track.
The 20-1 longshot, who started from the 16th of 19 gates, made a powerful run in the closing stretch to pass Nehro.
Mucho Macho Man finished third but favourite Dialed In never featured. Aidan O'Brien's Master Of Hounds ran respectably to finish in fifth.
A record crowd of 164,858 jammed the historic oval at Churchill Downs, south Louisville to watch the equine three-year-olds battle.
Shackleford, who eventually finished fourth, took the field along and was still in front turning into the straight when Nehro eventually wore him down, but his lead was only fleeting as Velazquez and Animal Kingdom quickened up in fine style down the centre of the track.
Animal Kingdom was competing in only his fifth race and not since Exterminator in 1918 has a horse won the Derby after so few career starts.
It was a first victory in 13 attempts at the American classic for Velazquez, a late replacement for Robby Albarado, who was injured in a midweek race.
Velazquez was originally booked to ride the one-time favourite Uncle Mo but looked set to miss the race when the horse was scratched on Friday.
"Words can't describe how I feel right now," said Velazquez.
"Of course I feel bad for Robby but this win is for the both of us - I know he is with me today.
"I've been unlucky with injuries and missed big winners before in the past but this time I got lucky. I've lost the last three favourites for this through scratchings.
"It was a bit tight at the first pole but I was soon happy and once I started my run I was always going to win."
By capturing the opener in the US Triple Crown series, Animal Kingdom will try to become the first horse since Affirmed in 1978 to sweep the treble that continues in two weeks at the Preakness and concludes at June's Belmont Stakes.
"This is an amazing horse," Motion said. "He's a very special horse and Johnny did a great job on him."