Jan Kirchhoff will move to Bayern Munich in the summer, while Ivan Klasnic and Alexander Ivanschitz's contracts will not be extended.
And the club have also announced that Radoslav Zabavnik and Marco Caligiuri are also going to be released this summer.
"I don't want to go into the reasons in public," said coach Thomas Tuchel. "We made this decision because we want to make changes.
"We are planning for the future without these two players and we want to change our perspectives, sporting and financial."
The players departing will make way for new ones arriving, general manager Christian Heidel has assured.
After Mainz's failure to qualify for Europe, Heidel is keen to build a side capable of achieving that objective next season.
"We have some spare places in the squad and we have some ideas as to how to fill them," he said.
"New players will be coming and it will be noticeable that we want to do something different."
Both Zabavnik and Caligiuri should get their swansong at the Coface Arena, though, with Tuchel unlikely to drop them just because they will be leaving next month.
Gladbach still have a very slight chance of qualifying for Europe next season, needing to make up four points on Freiburg in the last two games.
"First of all, we go to Mainz which will be a difficult game, but we desperately want to win there," captain Filip Daems said on the club website.
"Our destiny is no longer in our own hands so we shouldn't really make any big calculations.
"We just need to focus on ourselves. We want to get the most out of our remaining matches and, if our rivals slip up, we will gladly take it, but we cannot influence that any more."