Prof Sir Jonathan Van-Tam is leaving his role as England's deputy chief medical officer.
Health Secretary Sajid Javid said it had been "an honour" to work with the scientist and he was "hugely grateful for his advice".
Prof Van-Tam will continue to work for the government until the end of March.
He said it had been the "greatest privilege" of his professional career "to have served the people of the UK during this time".
The professor, who is leaving to take up a new role at the University of Nottingham, also said it had been the most challenging time of his professional career, especially the Covid response.
"We all wish Covid had never happened," he added, thanking all those he worked with during the pandemic.
Mr Javid paid tribute to the professor for the "vital role he has played in our vaccination programme" and wished him the best for the future.
"JVT's one-of-a-kind approach to communicating science over the past two years has no doubt played a vital role in protecting and reassuring the nation, and made him a national treasure," he said.
Prof Van-Tam was knighted in the most recent New Year Honours list, alongside Prof Sir Chris Whitty, chief medical officer for England and the UK government's chief medical adviser.
He has been the deputy chief medical officer for England since 2017 and became well-known for his colourful analogies during the government's coronavirus briefings, often appearing alongside the prime minister.
In late 2020 - while describing the early stages of the pandemic - he said "it's clear the away team gave us an absolute battering".
A year later, in November 2021, he warned "the final whistle hasn't blown" in the pandemic, but instead predicted we were in "half time of extra time".
"I love metaphors," he told the BBC in 2020. "I think they bring complex stories to life for people."
Prof Van-Tam had been on secondment to the Department of Health from the University of Nottingham. In his new role, he will be pro-vice-chancellor at the university's faculty of medicine and health sciences.
The 57-year-old lives with his wife and two teenage sons near Boston, Lincolnshire. He also has an older daughter. He is an avid fan of Boston United - perhaps explaining his choice of football-related metaphors.
