Bill Howatson joined the board as a non-executive director and took on the role of chairman in December 2011.
His resignation comes weeks after medical director Dr Roelf Dijkhuizen announced plans to retire from his post.
NHS Grampian has faced a string of major problems over the past few months and senior medics have made claims of a staffing crisis at the organisation. In a letter to staff, Mr Howatson said that it was now time for a new chairman.
He said: “I’m proud to have been able to play my part in bringing forward the integration of health and social care services in Grampian.
“I leave the organisation in the knowledge that we have achieved much for the people in the north east of Scotland. From delivering major capital projects to good clinical outcomes and quality care for patients.
“However, it is clear that NHS Grampian still faces significant challenges and I believe that to give future endeavours the best possible chance of success the health board should move forward under new chairmanship.”
The crisis-hit health board launched a recruitment drive to fill vacant posts earlier this year.
This came on the back of concerned consultants questioning whether doctors at Aberdeen Royal Infirmary were able to provide safe care after a locum consultant was flown in from India to provide full weekend cover for the A&E department.
The consultant was called in at short notice because the senior doctor scheduled to work the weekend shifts was off sick.
NHS Grampian previously stressed that the board was working hard to recruit new staff and admitted there were difficulties with rising living costs due to the success of the oil and gas industry.
Health secretary Alex Neil thanked Mr Howatson for his services to NHS Grampian and said: “I have accepted Bill Howatson’s resignation, with effect from December.
“NHS Grampian has made significant progress in a range of areas, for example, providing truly modern patient care in new state-of-the-art facilities and redesigning maternity services.
“The board continues to face challenges as it strives to meet the needs of local people and deliver safe and effective care.”
Scottish Labour’s health spokesman Neil Findlay MSP said: “We have known for some time that NHS Grampian has been under considerable pressures, from staff shortages to relationships between staff and management. Addressing these pressures must go beyond simply shuffling the personnel at board level.
“The health secretary must hold his hands up and admit the part the Scottish Government has played in contributing to the challenges NHS Grampian faces. It is in no small part due to the underfunding of NHS Grampian that these pressures have materialised.”