Clare Pelham, chief executive of Leonard Cheshire Disability, is to leave the charity after five years.
A spokeswoman for the charity said Pelham, who has no immediate role to move to, would stay in post until her successor was appointed and had no set date for leaving.
The spokeswoman said Pelham wanted to be open about her decision to leave before seeking a new position.
Pelham was appointed in 2010 after Eric Prescott, the charity’s previous chief executive, left with immediate effect after 18 months in charge.
Before joining Leonard Cheshire, Pelham was the first chief executive of the Judicial Appointments Commission, and also held senior civil service positions at the Cabinet Office, the Home Office and the Department for Constitutional Affairs.
She said: "I am proud of all the charity has achieved under my leadership in the last five years through its amazing staff and volunteers, and I am confident about its future. This has not been an easy decision to take, but I believe the time is right now for me to look for a new role.
"It has been a privilege to be chief executive of Leonard Cheshire. I have been a supporter of the charity since I was a student volunteer, and I will always continue to be a supporter."
Sally Davis, chair of Leonard Cheshire, said: "I want to thank Clare for her vision and commitment over the last five years. The trustees and I wish her well and are grateful for her immense contribution. A new chief executive will be recruited in due course and we will ensure a smooth transition."