Breitenreiter, who previously coached in the Bundesliga with Paderborn, Schalke and Hannover, led FC Zurich to the Swiss Super League title in 2021/22. The 48-year-old has signed a deal through to 30 June 2024.
"Andre Breitenreiter is a very ambitious coach whose attacking philosophy makes him an outstanding fit for TSG," said Hoffenheim director of football Alexander Rosen. "He stands for team spirit, passion and communication, and has been successful at all his previous clubs."
Breitenreiter moves to Hoffenheim fresh from guiding Zurich to their first Super League crown since 2009, while his new employers finished ninth in the Bundesliga at the end of Hoeneß's second and final season in charge.
Breitenreiter previously took Paderborn into the Bundesliga for the first time in the club's history in 2014, before spending the 2015/16 campaign at Schalke, securing a fifth-placed finish. He returned to management late in 2016/17, successfully steering Hannover back into the Bundesliga.
"I shall approach the job at Hoffenheim with great ambition," the former DFB Cup-winning midfielder told the club's website. "Their principles of being attacking, courageous, flexible and energetic completely match up with my philosophy of the game, so I'm looking forward to our future together and my return to the Bundesliga."
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