The 27-year-old has broken off negotiations over a new contract and will leave the Bundesliga club as a free agent this summer.
"Tranquillo has turned down our offer and he will leave us on June 30," said Bayer's general manager Wolfgang Holzhauser on his club's website.
"This is very regrettable because we wanted to extend his contract, but we could not reach an agreement financially."
A serious knee injury has kept the former Hannover midfielder on the sidelines for much of the last campaign, but he was a regular in the previous five seasons in which he made a total of 183 Bundesliga appearances.
It is not clear whether the 59-times Switzerland international has found a new club.