Plaza finished in a time of 4:30.36 to conclude the third stage, which encompassed the 183.1km route from Aguilar de Cam to Cervera del Pisuerga.
The Movistar rider, 33, stormed to victory in impressive fashion, showing himself to be the strongest rider on the slopes leading to the Parador de Cervera de Pisuerga.
Plaza's overall time in the general classification was 12:35.03, with Francisco Mancebo six seconds adrift and Francesco Lasca of Italy a further three seconds back.
After a thrilling day, Plaza jumped from the elite group just after the 2km banner to keep a slender advantage that, combined with the bonus seconds, allowed him to claim the stage and the overall win.
The rider from Alicante extended the Blues' domination in the event - Movistar also claimed the teams overall crown - with the last three editions being conquered by a rider from the team.
The victory puts to an end a long unsuccessful streak - his last victory came on stage six in the 2009 Volta a Portugal.
"It's been almost four years and, after everything I went through, it's a massive victory for me," Plaza said. "I knew my condition was good because I spent 10 days at home after the Volta a Cataluyna, training well and taking some rest - all feelings were good, but getting from that to winning a race... it's a really different thing."
Mancebo, also of Spain, put the US domestic team 5 Hour Energy on the map as he finished second.
Carlos Barbero of Euskadi came through to finish in third in the third stage, with Jose Rojas of Movistar ending up fourth.