On a grand stage and on a legacy-defining night, Briton Fury began well but was given a standing 10 count and saved by the bell after an Usyk onslaught in the ninth round.
In a tense wait for the scorecards to be read out, Fury appeared convinced of victory before a stoney-faced Usyk broke down in tears when he was confirmed as the winner.
The scorecards read 115-112 and 114-113 for the Ukrainian, with a third judge scoring it 114-113 to Fury.
It meant Fury, 35, lost for the first time in a 16-year professional career. He will get an immediate opportunity for revenge with a rematch planned for later this year.
"I believe he won a few of the rounds, but I won the majority," a defiant Fury said in the ring.
"It was one of the daftest decisions in boxing. I'll be back."
Usyk takes the WBC belt from Fury, to add to his WBA, WBO and IBF collection.
The 37-year-old remains unbeaten and is the first boxer in almost 25 years to stand tall as the sport's sole heavyweight world champion.
"Thank you so much to my team. It's a big opportunity for my family, for me, for my country. It's a great time, it's a great day," Usyk said.
"Yes, of course. I am ready for a rematch."
BBC Sport at Kingdom Arena, Riyadh