Andrew Flanagan, chief executive of the NSPCC, will stand down in March.
A spokeswoman for the children's charity said that Flanagan, who has been in the role for four years, was leaving for personal reasons. She declined to give any further details.
In a statement, Flanagan said it had been an "immense privilege" to have led the NSPCC.
"Not only have we created some of the most pioneering and innovative services for children in the UK, but we have broadened our ChildLine services online and into primary schools while ensuring every child contacting us gets an answer any time, day or night," he said.
"We are helping more children than ever before, demonstrating more clearly the impact we are having and striving ever more effectively towards our goal of ending cruelty to children."
In 2009, Flanagan launched a new seven-year strategy for the charity in response to financial challenges.
The strategy involved closing nine of its 120 services, which resulted in 45 job losses in 2009.
The following year, the charity announced that its 150 local service centres would close and 40 larger regional centres would open by 2013.
The charity’s income fell from £154.6m in 2009 to £148.6m in 2011, although it plans to increase its 2,000-strong workforce by 300 by 2016.
Mark Wood, chair of the NSPCC, said Flanagan had had a tremendous impact on the charity.
"He has created a clear direction and focus for us to achieve our ultimate aim of ending cruelty to children while ensuring the financial health of the NSPCC through difficult economic times – so important for a charity that depends largely on the generosity of voluntary donations from the public," said Wood.
"We extend our thanks to Andrew and wish him every success for the future."
The NSPCC is also looking for a permanent director of fundraising. Mike Parker, who had filled the role on an interim basis, stood down at the end of last month.
Parker stepped in last year after Paul Amadi, the NSPCC's previous director of fundraising, left to take up the same role with Diabetes UK.
The spokeswoman said the recruitment process was ongoing.