The DTM finale at Hockenheim on 8-9 October will mark the German's last race with the team, having been active with it since 2011.
Having made appearances in the DTM for the manufacturer in 2016, he was given a permanent seat for the 2017 season, taking the title in his rookie season.
Within four years, Rast won the championship title three times with Audi Sport Team Rosberg, winning 24 races and taking 20 pole positions.
After moving to Formula E for the 2019-20 and 2020-21 seasons, Rast made his DTM comeback this season with Team ABT Sportsline and is currently third in the standings as the best Audi driver.
He said the decision came with "a heavy heart" but added he "still has a few goals in motorsport that I want to achieve."
Rast said: "This decision was anything but easy for me. Audi has been my life over the past few years. We've worked fantastically together and celebrated many great successes.
"I'll never forget these moments, nor the many great people who made my victories and championship titles possible.
"Audi is a strong brand with fascinating cars like the Audi RS 6, which I was able to enjoy as a company car for many years. The Class 1 era in the DTM was the absolute highlight for me. The Audi RS 5 DTM, with its four-cylinder turbo engine, was a fantastic race car.
"Unfortunately, this era came to an end far too quickly. In both the Le Mans prototypes and Formula E, I also had the misfortune of having just joined the team when the programs ended. That was a real shame.
"I'm enjoying the DTM with GT3 race cars much more than I could ever have imagined. But I still have a few goals in motorsport that I want to achieve.
"That's why I have to say goodbye to the Audi fans with a heavy heart after the end of the 2022 season."
Rast began his Audi partnership competing with the Audi R8 LMS GT3 race car for Audi Sport customer racing, taking the ADAC GT Masters title in 2014 and victories in the 24-hour races at Spa (2012), the Nurburgring (2014) and Daytona (2012 and 2016).
In 2015, Rene Rast was also part of the Audi driver line-up at the Le Mans 24 Hours.
After the end of Audi's factory DTM commitment, Rast competed for the Audi Sport ABT Schaeffler team in Formula E, taking several podiums.
"What Rene Rast has achieved for Audi Sport, particularly in the DTM, is unique," says Oliver Hoffmann, Board Member for Technical Development at Audi.
"It is all the more painful that we have to let Rene go as a race driver after so many successful years together. Our motorsport program is currently being restructured completely as part of the electrification of the company.
"And Rene is also at a point in his career where he wants to set a new course. Rene Rast has a firm place in the history of Audi Sport and he will always remain a friend of the Audi family. We wish him only the best for his future."
Julius Seebach, Managing Director of Audi Sport GmbH and responsible for motorsport at Audi, added: "Rene Rast has long been underestimated. At Audi Sport, he was able to show that he is one of the world's best race drivers. Above all, his exploits in the Class 1 era of the DTM will always be closely associated with the four rings."
Rast was due to lead the development of Audi’s LMDh challenger for 2023 along with long-time DTM rival Nico Muller.
However, the project was unofficially scrapped at the beginning of the year, leading to Audi releasing Rast just one year into his two-year contract extension.
The news paves the way for Rast to return to Formula E next year, where he is being linked with the new McLaren entity that takes over the title-winning Mercedes operation.
