The American confirmed his decision on the eve of this year's United States Grand Prix, the first of two races held in his home country.
Spies used his personal Twitter account to link to a story on Superbike Planet, which quotes him as saying: "Yesterday I made a comment on Twitter to cause a stir. [Today] I'll be more in saying that I have chosen to leave Yamaha after this season for a litany of reasons.
"I will explain more when I feel it is appropriate. I'm discussing my situation with my sponsors and they are behind me. There are a few people at Yamaha who I hate to leave. And they know who they are. I wish Yamaha the best. I won't make any further comments until the official announcement comes out."
He then added in a separate tweet: "I'm extremely happy to push for the rest of the season to my fans and myself next year starts a new chapter. And yes I'm pumped!"
The American's decision brings a two-year spell with the works outfit to a close, and has huge potential ramifications in the 2013 rider market.
Spies has met with varied success in grand prix racing, earning rookie of the year honours in 2010 while racing for the Tech 3 outfit before moving to Yamaha's factory team to replace Valentino Rossi, and then claiming his first win in 2011 in the Dutch TT. This year he has struggled however, counting two fourth-place finishes as his best results.
His departure leaves the second works Yamaha seat, one of the most coveted rides in MotoGP, open for 2013.
Tech 3's Andrea Dovizioso, currently fourth in the riders' championship with four podiums to his credit, is an obvious candidate based on form.
The Italian recently fired a warning shot to the works team however, saying that he could consider alternative options.
Valentino Rossi is another name understood to be in consideration for the ride, with the Italian achieving unprecedented success with Yamaha between 2004 and 2010.
A potential move for Rossi could bring its own complications however, with sponsorship and his relationship with Jorge Lorenzo - fractured at best in his final two years at Yamaha - all questionable.
Spies meanwhile has not confirmed what he will do next year, but other MotoGP rides - namely at Tech 3 and Ducati – remain potential avenues, as does a switch back to the Superbike World Championship.