Moderator-designate Reverend Angus Morrison said he has made the decision reluctantly as he undergoes medical treatment.
A new appointment will be announced on April 2 ahead of the opening of the General Assembly on May 17.
The Church of Scotland said it is the first time in living memory that a moderator-designate has stood down.
Rev Morrison was due to take over the annual appointment from the Right Reverend Lorna Hood.
The minister of Orwell and Portmoak Church in Milnathort, Perth and Kinross, said: "This has been a very painful decision but deep down I feel it is the right one. I am undergoing medical treatment and anticipate an operation ahead.
"The demanding role of moderator requires someone to be operating on all cylinders. I do not have the necessary reserves just now.
"It is with huge regret and reluctance that I make this decision. My heartfelt prayers will be with all those on whom unexpected burdens now fall. May God's guidance, strength and peace be given to each one."
Rev Morrison, who is married and has four children, was ordained in the Free Presbyterian Church of Scotland but after ministries in Oban and Edinburgh transferred into the Church of Scotland and became the minister of St Columba's Old Parish Church in Stornoway before taking up his current post.
The moderator chairs the General Assembly of the Church of Scotland in Edinburgh each May, ruling on points of order and signing documents on its behalf.
The post is an honorary one, chosen by a committee of 51 members including previous moderators.
Rev John Chalmers, principal clerk for the Church of Scotland, said: "We ask the whole Church to remember Angus and his family in their prayers and we hope that his health is fully restored in due course.
"I know that the General Assembly will be enormously sympathetic to Angus's position and will no doubt want him to fulfil the role of moderator at some time in the future when he has made a full recovery."