The permanent secretary at the Ministry of Justice, Sir Richard Heaton, will stand down from his role this summer.
Justice Secretary Robert Buckland praised him as "exceptional", with the "strongest of reputations".
Sir Richard is the fourth senior civil servant to announce his departure in six months, among calls within Downing Street for reform of the service.
On Wednesday, Boris Johnson signed off a £250,000 pay out for the UK's most senior civil servant, Sir Mark Sedwill.
Sir Mark confirmed last month that he would leave Whitehall in September as Mr Johnson announced plans to split his role as cabinet secretary and national security adviser into two posts.
The change came after reports of tensions between him and senior members of the prime minister's team in Downing Street - but Sir Mark said the decision was "amicable".
Dominic Cummings, regarded as the prime minister's most influential political adviser, has long called for an overhaul of the civil service.
Sir Richard has been at the Ministry of Justice since 2015, and was permanent secretary at the Cabinet Office for the three years.
He first came to Whitehall in 1991 as a legal adviser to the Home Office, and has worked across multiple departments advising on criminal law, the constitution, and human rights law.
Speaking ahead of his exit, Sir Richard said it had been "a privilege" to lead at the Ministry of Justice, despite "challenging years" - especially with the coronavirus outbreak.
"But what I am most proud of is the way in which people from every part of the department and its partner organisations work together to get things done," he added.
Who else has resigned?
Sir Philip Rutnam resigned as Permanent Secretary of the Home Office in February, announcing he would take the Home Secretary Priti Patel to an employment tribunal.
He said there had been a "vicious and orchestrated" campaign against him in the department - accusations Ms Patel has denied.
And Sir Simon McDonald announced in June he would step down in as permanent secretary of the Foreign and Commonwealth Office in September "at the request" of the prime minister.
His exit comes ahead of the department's merger with the Department for International Development.