NHS chief executive Amanda Pritchard will step down at the end of this financial year in March.
A source said the move was her own decision and she is not happy with government plans to strip NHS England of its independence and give the Department of Health more control.
Ms Pritchard – who has come in for criticism from MPs in recent weeks – said it had been a “hugely difficult decision for me to stand down”.
She added: “It has been an enormous privilege to lead the NHS in England through what has undoubtedly been the most difficult period in its history.”
NHS England said that, having discussed everything with Health Secretary Wes Streeting in recent months, Ms Pritchard had “decided now is the right time to stand down”.
It said the NHS has “turned a corner on recovery from the pandemic and the foundations are in place to make the necessary changes to the centre to best support the wider NHS”.
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Sir James Mackey will be taking over from April.
Ms Pritchard was forced to defend herself last month when asked about critical comments made by MPs.
A damning report concluded that NHS and Department of Health officials are complacent and “out of ideas” when it comes to transforming the health service for patients.
She was challenged about the report during an evidence session in Parliament but after the meeting, MPs on the committee expressed “frustration” over “lengthy and diffuse answers”.
Speaking to BBC Breakfast on February 13, Ms Pritchard was asked whether she was the right person to lead the health service and she said: “We are far from complacent."
But she added “we’re not all brilliant performers at committee hearings”, saying: “We welcome that scrutiny, and I welcome the opportunity to be able to keep talking to committees and others about the work we are doing, and staff are doing now, to keep trying to make things better."
Ms Pritchard became the NHS top boss on August 1 2021, taking over Lord Simon Stevens.
She was the first woman to hold the position in history, since it was created in 1985.
She took over in the midst of a third wave of Covid-19 and as the NHS already faced an unprecedented backlog of care.
Ms Pritchard is a married mum-of-three who has been working in the NHS for 25 years.
She joined the NHS through the graduate management training scheme in 1997 after studying at Oxford University.
And since then, Ms Pritchard has held a number of key roles across the health service, including running the busy London trust Guy’s and St Thomas’ and as chief executive of NHS Improvement.
She also served as a health team leader in the Cabinet Office’s delivery unit and in the past two years, worked as chief operating officer under Lord Stevens.