Golden Soul was second, followed by Revolutionary.
Orb, the post-time favorite at 5-1, had a winning time of 2:02.89 over the muddy 1¼-mile track.
“When it was time to go, I knew he was going to respond well,” jockey Joel Rosario said of Orb, calling his race a “perfect trip.”
Shug McGaughey III, a Kentucky native and widely respected trainer who had yet to win the Derby, was overcome with emotion by Orb’s comeback, breaking down as he tried to explain his joy.
“I always dreamed of this day and it finally came,” said McGaughey.
Orb’s co-owner Stuart Janney gave McGaughey the credit, noting that many had been saying his time to win the Derby had come.
“We certainly hoped it had,” Janney said. “And it did.”
Palace Malice, ridden by veteran rider Mike Smith, broke out to a several-lengths lead about halfway through the race.
The lead group tightened leaving the backstretch, with Normandy Invasion briefly taking the lead before Orb made his move.
More than 150,000 spectators packed Churchill Downs in Louisville, where rain had fallen much of the day and left the track sloppy.
The Derby, which features the nation’s finest 3-year-olds, is the first jewel of the Triple Crown. The 138th running of the Preakness, on May 18 in Maryland, is the second, followed by the Belmont Stakes, in New York on June 8.
Only 11 horses have won the crown, none since Affirmed did in 1978.
Two riders were trying to make history Saturday, but came up short.
Goldencents was ridden by Kevin Krigger, who vied to become the first black jockey to win the premier race since Jimmy Winkfield took the trophy back-to-back in 1901 and 1902.
Rosie Napravnik, 25, riding Mylute, made a bid to be the first female jockey to win the race. Mylute finished fifth.
It was the first Kentucky Derby win for Rosario.