Anne McGuire said that after five years as first the minister, then the shadow minister for the disabled, it was time to allow someone else to take on the role.
The MP for Stirling served as the Opposition leader's parliamentary private secretary (PPS) for the first year of his party leadership and said that had been "a pleasure and privilege".
She said she would continue campaigning against an "unprecedented attack" on the disabled by the Government and parts of the media as a backbencher and co-chair of the all-party disability group.
She told the LabourList website that she asked in July to step down from the front bench at the next reshuffle - which is expected next week.
"In 2010, I was delighted to be asked by Ed to be his one of his PPSs after his election as leader and it was a pleasure and privilege to work with directly with him and I look forward to seeing him elected as Prime Minister in 2015."
Mr Miliband said: "Anne was a brilliant Minister for the Disabled, a fantastic PPS to me and a great member of the shadow front bench."
She follows shadow justice minister Rob Flello through the shadow cabinet exit after he resigned this week because other political interests meant he felt unable to "give everything the 100% I wanted to".
It is not yet known if Ms McGuire, 64, intends to stand at the next general election in 2015.