O'Neill, a former Goldman Sachs chief economist who was brought in by former prime minister David Cameron, also resigned as the Conservative party whip. He did not give a reason for his departure but UK media reports indicate it was a result of growing tensions with May's approach.
There had been growing speculation over Lord O'Neill's resignation following a report in the 'Financial Times' in July that cited his unhappiness after May announced a shock review into the 18-billion-pound Hinkley Point project involving China.
"The case for both to be at the heart of British economic policy is even stronger following the referendum, and I am pleased that, despite speculation to the contrary, both appear to be commanding your personal attention. I am leaving knowing that I can play some role supporting these critical initiatives as a non-governmental person," he adds.
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He will now sit on the cross-benches of the House of Lords.
May said she was sorry about O'Neill's resignation and thanked him for his service.
"You have made a significant contribution to driving forward the government's work on delivering growth beyond the south-east through the northern powerhouse and on promoting stronger economic links with emerging economies, including China and India. You have laid important foundations in these areas, and the government will build on them," she wrote.
You should take great pride in seeing your review culminate this week in the UN high level agreement.
"You have played a vital role in building global consensus on this important issue, which will have long-lasting benefits."
Downing Street announced that Lord Young of Cookham will become the new Treasury spokesman in the House of Lords.