Kameko beat Wichita (15-2), with Frankie Dettori in the saddle, by a neck over the Rowley Mile in the first classic of a British flat season disrupted by the COVID-19 pandemic.
Pinatubo, the 5-6 odds-on favourite, finished third and a further length adrift in the field of 15.
The race was run without spectators, and with jockeys wearing face masks.
"I've never won a Classic in Britain and this means the absolute world to me, for everyone connected with this horse as well," said Murphy after Kameko, now installed as a favourite for July's Epsom Derby, became the fastest Guineas winner ever.
"It's the stuff of dreams... around four furlongs he got a little bit lost but he came home really well. It was a gutsy performance."
Godolphin-owned Pinatubo, named after a volcano in the Philippines and trained by Charlie Appleby, had finished last season as the highest-rated juvenile in a quarter of a century.
Rated a wonder horse in the making and unbeaten in six starts, the colt was making his debut as a three-year-old ridden by William Buick. (Reporting by Alan Baldwin, editing by Christian Radnedge)