Simon Wren-Lewis began his career as an economist in H.M.Treasury. In 1981 he moved to the National Institute of Economic and Social Research. From 1988-1990, as Head of Macroeconomic Research, he supervised development of the Institute's domestic and world models. In 1990 he became a professor at Strathclyde University, from 1995 he was at Exeter University, and in 2007 moved to the economics department (and Merton college) at Oxford. He has published papers on a wide range of macroeconomic issues in leading academic journals.

Academic work has often had a strong policy focus. In 1989 he published, with colleagues at the National Institute, a study suggesting that an entry rate of 1.95 DM/£ into the ERM was too high. In 2002 he wrote one of the background papers for the Treasury's 2003 assessment of its five economic tests for joining EMU. He was also the principal external advisor to the Bank of England on the development of their core macroeconomic models. A long time advocate of Fiscal Councils, his 2007 proposal was influential in the formation of the UK‘s Office of Budget Responsibility. Since 2012 he has published a blog which is widely read among UK and international policymakers