Ricky Stenhouse Jr. will take Kenseth's spot for the 2013 Sprint Cup Series season.
There has been speculation Kenseth would hook up with Joe Gibbs Racing next season, replacing either Joey Logano or be the driver for an added car.
Logano is in the last year of his contract with Gibbs.
Kenseth, 40, has been with Roush Fenway since 2000. He is the current points leader, with 11 Top-10 finishes in 16 starts this year, including his second Daytona 500 title.
Kenseth expressed appreciation for the opportunities Roush Fenway afforded him through the years.
"Together we have enjoyed a lot of success," Kenseth posted on his Twitter account. "And as a team we are committed as ever to the remainder of the 2012 season and chasing a 3rd Sprint Cup title for (team owner) Jack (Roush) and RFR. Although I have nothing to announce regarding 2013, I feel the timing of this announcement gives RFR ample time to get things lined up."
Roush Fenway did not explain Kenseth's departure.
"I'd like to thank Matt Kenseth for his many years of loyal service," Roush said in a statement. "Matt has been an integral part of this organization for well over a decade, and we are extremely appreciative of his accomplishments and contributions to the team, and will always consider him a part of the Roush Fenway family."