Anthony Fauci will step down as head of the National Institute of Allergy and Infectious Diseases (NIAID) and chief medical adviser to President Joe Biden.
Dr Fauci, who served as director of the NIAID for 38 years, said he would leave both positions in December to “pursue the next chapter” of his career.
“It has been the honour of a lifetime to have led the NIAID,” Dr Fauci, 81, said in a statement.
He became the face of the nation’s Covid-19 response during the pandemic.
On Monday, Mr Biden thanked him for his “spirit, energy, and scientific integrity”.
“The United States of America is stronger, more resilient, and healthier because of him,” the president wrote in a statement.
In July, Dr Fauci said he would retire before the end of Mr Biden’s current term.
Dr Fauci first joined the National Institutes of Health in 1968, when Lyndon Johnson was president.
He was appointed to director of the NIAID, the infectious national disease branch, in 1984, while the AIDS epidemic raged. He has served under seven presidents since – from Republican Ronald Reagan to Democrat Joe Biden.
It wasn’t until 2020, with the onset of the coronavirus pandemic, that he became the most famous doctor in America.
Dr Fauci became a frequent media presence in the US and abroad as he emerged as the face of America’s fight against coronavirus. He also became polarising figure during that time.
While he gained fans – a petition to name him People magazine’s “Sexiest Man Alive” in 2020 gathered more than 28,000 signatures – he also angered some on the right who saw him as the public face of lockdowns and mask mandates.
And he occasionally clashed with former president Donald Trump over the pandemic response.
Though Dr Fauci is leaving government, he made clear on Monday that he was not retiring from medicine altogether.
“I plan to pursue the next phase of my career while I still have so much energy and passion for my field,” he said.
Dr Fauci, who will turn 82 on 24 December, did not set an exact date for his departure.