Micklethwait was educated at the independent school Ampleforth College and Magdalen College, Oxford, where he studied history. He joined The Economist in 1987, previously having worked for Chase Manhattan Bank for two years.

Prior to becoming editor-in-chief, he was United States editor of the publication and ran the New York Bureau for two years. Before that, he edited the Business Section of the newspaper for four years. His other roles have included setting up an office in Los Angeles for The Economist, where he worked from 1990 - 1993. He has covered business and politics from the United States, Latin America, Continental Europe, Southern Africa and most of Asia.

A frequent broadcaster, he has appeared on CNN, ABC News, BBC, C-Span and NPR. He is the co-author of several books with Adrian Wooldridge, also a journalist at The Economist, including:

In A Future Perfect, they resurrected the term "cosmocrat".

Appointed as editor-in-chief on March 23, 2006, the first issue of The Economist published under his editorship was released on April 7, 2006.