In front of empty stands, normally packed with 100,000 spectators, the 25/1 shot, ridden by Emmet McNamara, stormed home ahead of the 16-strong field.
The horse, owned by Mrs John Magnier, Michael Tabor and Derrick Smith, is by Galileo, trainer Aiden O’Brien’s first Derby winner.
Serpentine’s victory gave O’Brien an eighth record-breaking Derby win. He had six runners in last Saturday’s race.
The previous week the horse had his first win in only three runs at Curragh and at Epsom he gave McNamara his own first win in nine months.
The one-mile, four-furlong race was run on good ground and Serpentine went clear five furlongs from home, gaining a 12-length lead.
His lead was reduced but McNamara rode him on and he passed the post five and a half lengths ahead.
O’Brien told The Guardian: “We try to give every horse the best chance of winning and we try to ride them all accordingly.
“Emmet was very happy to go forward and William Buick, on Amhran Na Bhfiann, was happy to go forward, too.
“When he won impressively last weekend, he absolutely ran through the line at the Curragh at a mile and a quarter and to do that you have to be very good and have real class.
“Donnacha, my son, said that, after five furlongs, he was in front, very comfortable and he wasn’t going to stop.
“Emmet judged the pace really well and he knew he was a horse which was going to get every yard of a mile and a half.”