Home Secretary John Reid says he will leave the Cabinet in June when "Tony Blair goes".
Mr Reid also ruled out a challenge to Gordon Brown for the Labour leadership, ending months of speculation.
He told BBC One's The Politics Show he would vote for Mr Brown as leader, but would return to the backbenches rather than serve in a Brown cabinet.
The announcement means Mr Brown will not face a top-level challenge for the Labour leadership.
Mr Blair is expected to announce a timetable for his departure on Thursday, but will remain as prime minister until a new Labour leader - now almost certain to be Gordon Brown - is elected.
Mr Reid said it was a "natural break period".
"Now I've done nine jobs in 10 years and I think from my point of view I think it's a good thing to be able to go out to listen, to learn, to discuss, to get back to the grass roots.
"But also from the point of view of an incoming prime minister. I think the new prime minister should have the maximum flexibility. He needs space."
BBC news website political correspondent Nick Assinder said Mr Brown and Mr Reid "were not friends".
"Indeed Mr Reid's opposition to Mr Brown was verging on the legendary, and the home secretary had previously joked he might end up as Mr Brown's tea boy after the succession," he said.
Asked whether he was jumping before he was pushed, Mr Reid said: "I have discussed it with Gordon, I've had a very good discussion with Gordon on a number of these issues.
"He has made plain to me there's a place in his government for me but he understands and he accepts my decision on this.
"I have made plain to him that from the backbenches I will be there to support him, it will not be a case of sniping, it will be a case of sustaining the Labour government and the new prime minister."
He added; "From my point of view, it is better to take the chance, having had nine jobs in 10 years, to recharge my batteries."
In a letter to the prime minister, Mr Reid said: "Whatever the pros and cons of a contest, I do not believe that there is eagerness in the party for what might be a divisive exercise at this time."
In a letter of reply, Mr Blair said he respected Mr Reid's decision but said it would be "a great loss to both country and party".
Mr Reid has held several ministerial positions since 1997, including transport minister, Northern Ireland secretary, Labour chairman, health secretary and defence secretary.
He replaced Charles Clarke as home secretary last year, promising to revamp the crisis-torn department he said was not "fit for purpose".
1997: Armed forces minister
1998: Transport minister
1999: Scottish Secretary
2001: NI Secretary
2003: Labour Chairman
2005: Defence Secretary
2006: Home Secretary
He has said he will see through reforms to the department, which is to be split in two, before standing down.
Other Blairite heavyweights to have ruled themselves out in recent weeks include Environment Secretary David Miliband and Mr Reid's predecessor at the Home Office Charles Clarke.
Mr Brown could still face a challenge from one of two left-wing backbenchers - John McDonnell and Michael Meacher.