Starmer has vowed to never walk away after facing the biggest challenge to his authority yet, including a call from Labour's leader in Scotland for him to stand down over the appointment of Mandelson, who was close to the late US sex offender Jeffrey Epstein.
"I am very grateful to Sir Chris for his long and distinguished career of public service, spanning more than 35 years, and for the support that he has given me over the past year," Starmer said in a statement on Thursday.
"I have agreed with him that he will step down as Cabinet Secretary today," he added.
Wormald was appointed to the post in December 2024, the most senior role in the civil service - the permanent non-political government workforce.
He said it had been "an honour and a privilege to serve as a civil servant for the past 35 years".
He follows Starmer's closest aide Morgan McSweeney and communications chief Tim Allan in leaving office in a matter of days after the Epstein files revealed the depth of the relationship between Mandelson and Epstein, prompting renewed questions over Mandelson's appointment.
Mandelson has said he does not recall having received payments from Epstein and has not commented publicly on allegations he leaked documents.
He did not respond to messages seeking comment.
Wormald's departure will also mark a broader reset in Starmer's government, which has long trailed the populist Reform UK in the polls as it struggles to deliver on its policy priorities and has made several U-turns on areas such as welfare reform.
