The Work and Pensions Secretary who has held the position since 2010 made the announcement on Friday evening amid a Conservative row over the Budget.
The former Conservative leader said that plans to cut the benefits paid to the disabled by more than £1 billion were a "compromise too far" and said that welfare for pensioners should be cut instead.
The planned cuts are to hit Personal Independence Payments, expected to affect 640,000 people.
Mr Duncan Smith said the cuts were "not defensible" within a Budget that "benefits higher earning taxpayers".
He said he is proud of reforms made over the last five years, but that the latest cuts were a "compromise too far".
In a letter he wrote: "I am unable to watch passively whilst certain policies are enacted in order to meet the fiscal self-imposed restraints that I believe are more and more perceived as distinctly political rather than in the national economic interest.
"I have for some time and rather reluctantly come to believe that the latest changes to benefits to the disabled and the context in which they’ve been made are a compromise too far.
"While they are defensible in narrow terms, given the continuing deficit, they are not defensible in the way they were placed within a Budget that benefits higher earning taxpayers.
"They should have instead been part of a wider process to engage others in finding the best way to better focus resources on those most in need."
The MP for Chingford continued: "Those reforms have helped to generate record rates of employment and in particular a substantial reduction in workless households.
"Throughout these years, because of the perilous public finances we inherited from the last Labour administration, difficult cuts have been necessary.
"I have found some of these cuts easier to justify than others but aware of the economic situation and determined to be a team player I have accepted their necessity."
Tory MPs are openly rebelling over the plans to slash £1.2billion from Personal Independence Payments (PIP) by removing weekly payments from people who need 'aids and appliances' to help them dress and use the toilet.
Labour has demanded the Government abandon the plans and promised to force a Commons vote.
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