Miss Hughes said that she was stepping down for "personal reasons".
She claimed her departure had nothing to do with the ongoing MPs' expenses scandal.
Her announcement followed a similiar statement from Patricia Hewitt, the former Cabinet minister, who is also standing down.
Miss Hughes, the MP for Stretford and Urmston, also said she would be leaving the Government at a reshuffle, expected after this week's Euro and local elections.
In a letter to Prime Minister Gordon Brown, Miss Hughes said: "I would not have chosen the current appalling climate to announce my decision when so many Members are resigning for reasons to do with their Parliamentary allowances.
"I want to make it absolutely clear that this has nothing whatsoever to do with my decision or the reason for making it public now."
The Telegraph disclosed how Ms Hughes rented a second home in London where she claimed £801.60 for re-upholstering furniture, £718 for a chair and £435 for curtains and bedding.
But, in her letter to Mr Brown, she stressed that her decision to leave Parliament and Government was purely for family reasons.
She told him he was "widely expected" to conduct a reshuffle "very soon".
"I know you are already aware of some of the family circumstances that lie behind my decision and I appreciate very much the personal interest you have shown in this," she said.
"However there are, in fact, a number of personal and family issues which, taken together, are such that I cannot make the commitment to be in Parliament and away from home for a further five years beyond the next general election.
"I now want to be at home much more than being a minister or MP will ever allow."
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