Justin Forsyth, chief executive of Save the Children UK since September 2010, is to leave the charity in February.
In an email to staff today announcing his departure, Forsyth said that, after five years, it was right for him and the charity that he moved on.
He said he had made the decision with a "mix of pride in what we have achieved and sadness at moving on from one of the best jobs in the world".
He told Save staff that he hoped to take a short break before moving on to the next step in his career.
"I have a few exciting irons in the fire that are too early to talk about, but I will keep you posted," he wrote.
Forsyth said he had been considering moving on for several months and had been talking to Sir Alan Parker, who was then chair of Save the Children UK, "since before the summer" about the possibility.
"The last few years have not always been easy," Forsyth told Save the Children staff. "What we have achieved is the result of blood, sweat and tears. We have operated under the spotlight with much more intense external scrutiny.
"On a personal note, I know I have not always got everything right. We could have given more priority to some crucial areas and done some things better. You learn a lot in these jobs about yourself and leadership."
Forsyth, a former adviser to Tony Blair, apologised earlier this year after Save the Children US gave a global legacy award to the former Prime Minister.
Forsyth said at the time: "I know that many of our supporters and volunteers were very upset – several of our staff, too – and I’m very sorry for that. But this was an award given by our sister organisation in the United States.
"It’s a very different political context there, and they’ve had hardly any complaints. And, yes, it was a global legacy award. It was called that. But actually it was an award very, very specifically for Tony Blair’s efforts on Africa at two G8 summits in Birmingham and Gleneagles, not his wider legacy."
Forsyth was among the four charity chief executives who were called to give evidence to MPs on the Public Administration and Constitutional Affairs Committee as part of its continuing inquiry into charity fundraising.