The 192km mountain stage from Trujillo culminated with two ascents of the first category Alto de Piornal and it was here where he secured victory.
He pulled ahead of nearest General Classification challenger Enric Mas after the duo had caught stage leader Robert Gesink (Jumbo-Visma) with just under half a kilometre left, stretching his overall lead to two minutes seven seconds over the Spaniard.
"It's a perfect day, this was the most perfect day ever," Evenpoel told reporters.
"Winning on a mountain top in the red jersey is amazing. It was a tough stage and hard work at the end. I learned we have to always stay calm, even in the last kilometre we were 15 or 20 seconds off the lead, but we caught him and I went with 200 metres to go."
"It's still not done, there's one really hard stage to come and they will attack me, but maybe now it's easier to control as my legs feel really good."
The day had started with a large crash in the peloton after which Jay Vine (Alpecin-Deceuninck) abandoned and left a number of riders sporting road rash.
A mass breakaway ensued, with 38 riders leading the course until the first ascent of the Piornal with just over 50 kilometres to go, where the group splintered and Gesink pulled out in front, leading until the final stages before finishing third.
Friday's stage is a 138km loop starting and ending in Talavera de la Reina, featuring two ascents of the second category Puerto de Pielago before a flat finish.
