Meanwhile pursuing these academic interests, Wilber served as a United States intelligence officer with the Office of Strategic Services (OSS), and was an active participant in the power struggles of nations, especially during the rivalry between the United States and the Soviet Union in Iran after World War II. He is best known as the architect of the CIA project "Operation Ajax", a successful plot to overthrow the government of Iranian Prime Minister Mohammad Mossadeq. The plot replaced Iran's first democratically elected leader with the monarchy of Mohammad Reza Shah Pahlavi.
His memoir, which partially recounts his role in the coup, is titled: Adventures in the Middle East and Iran, Past and Present and Iran Past. As the principle planner of Operation Ajax, Wilber deeply resented the way he was treated in Kim (well really, Kermit) Roosevelt's book, Counter Coup: The Struggle for the Control of Iran. In 1957, Wilber founded Middle East Research Associates, meant to be a vehicle for Don to cash in on his knowledge of the oil region. This was not known to be a CIA front. However, the venture was never a great success (which probably proves it wasn't a CIA front!).