The 20-year-old Evenepoel had led the general classification after winning Thursday's 150-km third stage between Sargentes de la Lora and Picon Blanco. He finished with an overall time of 19 hours, 14 minutes and 42 seconds.
"This is a perfect day," Evenepoel told reporters. "The team worked perfectly, kept me in position and it was my job to finish it. I'm glad it worked out. This was my third stage race this season and I'm winning for the third time.
"It was harder than two days ago when I won the stage, but luckily I had a good team around me and got the job done."
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Evenepoel won the Vuelta a San Juan and the Volta ao Algarve before the COVID-19 shutdown.
Spain's Mikel Landa (Bahrain–McLaren) was 30 seconds behind Evenepoel overall after completing the 158-km fifth stage in second place behind winner Ivan Sosa (Team Ineos).
It was Sosa's third straight victory in the mountain stage of the Spanish race, with the 22-year-old Colombian finishing in a time of three hours, 47 minutes and 56 seconds.
"I knew the climb very well and I knew I had to wait until the final ramp. I was at the limit, and everything turned out well," Sosa said.
"We're all happy we're back to racing with this situation."
Landa attacked with 4km left in the ascent at the end of the stage but Evenepoel staved off the challenge.
Evenepoel was joined on the podium by team mate Joao Almeida, who finished third overall. (Reporting by Shrivathsa Sridhar in Bengaluru Editing by Toby Davis)
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