Mark Golding's decision to stand down as chief executive comes after the charity was embroiled in a major sex scandal involving Oxfam workers in Haiti following its devastating earthquake.
He had faced criticism for his handling of the claims that Oxfam aid workers in Haiti in 2011 had used prostitutes.
The Oxfam scandal dominated the British national media for days, and attracted global publicity, but a spokeswoman for the charity said his resignation was "absolutely not to do with his handling" of the crisis.
In February Goldring's deputy, Penny Lawrence, resigned over the charity's handling of the sex scandal which led to the British Charity Commission launching a statutory inquiry into Oxfam.
Goldring said in a statement issued by the charity: "Oxfam has achieved much, bringing humanitarian assistance and new opportunities to millions of people in some of the hardest places on the planet, shining a spotlight on the barriers that trap people in poverty and holding those in power to account for decisions that affect the world's poorest people. I am proud to have played a part in that, but I think the time is coming for a new leader.
"Following the very public exposure of Oxfam's past failings, we have redoubled our efforts to ensure that Oxfam is a safe and respectful place for all who have contact with us. We are now laying strong foundations for recovery. I am personally totally committed to seeing this phase through.
"However, what is important in 2019 and beyond is that Oxfam rebuilds and renews in a way that is most relevant for the future and so continues to help as many people as possible around the world build better lives. I think that this journey will best be led by someone bringing fresh vision and energy and making a long-term commitment to see it through."
Goldring will leave the organisation at the end of this year.
In 2016 Goldring oversaw the biggest annual humanitarian response in Oxfam's history, encompassing the refugee crisis as well as conflicts including Yemen, Syria and South Sudan. During his five years in post he has also overseen the growth of Oxfam's work tackling poverty and its root causes and ensured Oxfam improved its safeguarding practices following sexual abuse by former staff in Haiti in 2011.
Caroline Thomson, chair of Oxfam, said: "It is with great sadness and with thanks for his dedication and leadership that I accepted Mark's decision to stand down.
Thomson said Goldring had faced the test of a lifetime managing the crisis which the charity in February and related to events before he joined.
"He rose to the immense challenge and his leadership has been invaluable through it. It is testament to his integrity and humility that Mark will see through the next few difficult months," she added.