Richard Greenhalgh, the chairman of the college's governing council, is to leave in the summer, and Heather Du Quesnay, the chief executive, will depart next year.
The move comes as the national college awaits the publication of what is expected to be a critical report into its work and functions by the Department for Education and Skills. No dates have yet been set for its release.
Mr Greenhalgh, who is the chairman of chemicals giant Unilever UK, said he had taken the decision to leave last year.
He said: "I agreed nine months ago that I would step down after four years in the post and that position has now been advertised and the selection process is going on. I am also retiring from Unilever."
He said his departure was not linked to the report, which he described as "a stock-take" of the college's move from adolescence to adulthood.
Ms Du Quesnay will leave after five years at the college.
She said: "During the time I have been at the college we have put school leadership on the map. We started from nothing, but now the college has won the respect and regard of the teaching profession and many others outside education who recognise the importance of leadership.
"The college is making a positive difference to the attainment of children in the nation's schools. I am enormously proud of what my team is achieving.
"I am considering a number of new opportunities and looking forward to what they might offer."
Charles Clarke, the Education Secretary, praised Ms Du Quesnay's role in establishing the college. "Heather has created from scratch an organisation which is now making a substantial contribution to the development of school leadership across the country," said Mr Clarke.