Evenepoel, 22, won the Basque event for the second time, three years after his first success.
Frenchman Pavel Sivakov took second place, nearly two minutes away, ahead of Belgian Tiesj Benoot, more than two and a half minutes away.
Evenepoel, winner of Liège-Bastogne-Liège in April, had not raced since winning the title of Belgian time trial champion on June 23.
The young Belgian followed a three-week course at altitude in northern Italy to prepare for the Vuelta, his big goal for the second half of the season.
In the Basque Country, the riders of the Tour de France accused the fatigue of the three weeks of racing.
Among others, the Slovenian Tadej Pogacar, who was left behind in the climb of Jaizkibel 63 kilometers from the finish, and the Frenchman David Gaudu.
Evenepoel caused the decision in Erlaitz, the main difficulty of the course (4 km at more than 10%).
The Briton Simon Yates kept his wheel at first before stalling, being caught by the first pursuers and finally finishing sixth.
© 2022 AFP