Martin Barkley, 61, said the decision to leave the Tees Esk and Wear Valleys NHS Foundation Trust (TEWV) after eight years had been a "difficult one".
He has worked for the NHS for more than 40 years.
The trust said a recruitment process to select a new chief executive would begin in February.
Mr Barkley said: "After so many years with the trust and other mental health and learning disability organisations the time has arrived for a change."
The trust runs mental health services in County Durham, the Tees Valley and much of North Yorkshire.
In October, it took over services in York just days after the Care Quality Commission (CQC) ordered the city's psychiatric hospital, Bootham Park, to close after an inspection found it to be "unfit".
Mr Barkley said his decision to leave the trust had nothing to do with the problems surrounding mental health provision in York.
He said the trust remained committed to working with the Vale of York Clinical Commissioning Group to provide a new hospital for the treatment of people with mental health problems in the city.
The chief executive of a mental health trust which serves parts of the North East and Yorkshire, is to stand down in April.