The 24-year-old broke away from a reduced group with 10km to go and managed to increase his gap to the chase group up to the finish, managing to hold off Michael Woods (Cannondale-Drapac) and Paris-Nice winner Sergio Henao (Team Sky).
Orica has managed to get Roman Kreuziger in the early breakaway of the 186km race, which acts as a precursor to the Tour of the Basque Country on Monday.
When that break was eventually caught with 50km to go, numerous attacks came on the following climbs, with none sticking.
It wasn’t until 20km to go that a nine man group was able to jump clear, with Yates and his teammates Damien Howson and Carlos Verona managing to make it in.
The gap back to peloton held at around 30 seconds, before Yates was able to make the decisive attack with 10km to go.
“It was a hard race today, at the start with the wind and the rain but the team rode really well, protecting me at all times,” Yates said.
“Roman Kreuziger went into the main break which was great for us, it meant we could sit in the wheels and save energy.”
“On the climbs the guys were always there and we made it a hard race so I am extremely happy to win today.
“Next I have Pais Vasco and I hope I can ride well there and maybe get another victory, I am looking forward to it.”
It’s Yates’ second win of the season after he broke away to take a stage win at Paris-Nice in March.
Gran Premio Miguel Indurain
1. Simon Yates (Orica-Scott), in 4-34-01
2. Michael Woods (Cannondale-Drapac), at 23s
3. Sergio Henao (Team Sky), at 23s