After an exciting lead for Aiken's Palace Malice, Orb pulled ahead to win the Run for the Roses.
Palace Malice of Dogwood Stables, run under president W. Cothran Campbell, led the pack for a while until the group entered the final stretch.
Orb then splashed through the slop to win the Kentucky Derby.
Palace Malice finished in the No. 12 spot.
Orb's win gave Hall of Fame trainer Shug McGaughey his first victory in the 3-year-old classic.
When the field turned for home on the cool, overcast Saturday afternoon at Churchill Downs, Normandy Invasion grabbed the lead from Palace Malice while Orb was gearing up. But in the deep stretch, Orb prevailed, carrying Joel Rosario to his first Derby win.
Long shot Golden Soul was second with Revolutionary third. Normandy Invasion faded to fourth.
Orb, the 5-1 favorite, ran the 1¼ miles in 2:02.89.
Todd Pletcher had a record-tying five runners. Revolutionary was the best of the "Todd Squad," followed by Charming Kitten (ninth), Overanalyze (11th), Palace Malice (12th) and Verrazano (14th).
Goldencents, owned in part by Rick Pitino, coach of Louisville's national basketball champions, finished a 17th. His jockey, Kevin Krigger, was trying to become the first black rider to win the race since 1902.
Pick up a copy of Sunday's Aiken Standard for full coverage of the Kentucky Derby and Palace Malice.
— The Associated Press contributed to this report.