Though his resignation was long expected, the timing of the announcement was not - coming amid plans for him to visit the Middle East after the death of Palestinian leader Yasir Arafat.
As head of the Joint Chiefs of Staff, Powell was the military architect of the 1991 Gulf War effort to force Iraqi forces out of Kuwait.
He saw a turbulent four years as secretary of state marked by the 11 September 2001 attacks and the Iraq invasion.
Pursuing a pragmatic policy of multilateral diplomacy, he reportedly clashed frequently with administration hardliners such as Cheney and Defence Secretary Donald Rumsfeld who favoured unprovoked military action.
But he refused to talk publicly about the tensions or his future intentions, repeatedly telling reporters: "I serve at the pleasure of the president."
Many reports said Powell had felt personally wounded after giving a presentation to the UN Security Council on 5 February 2003 on the US case for an invasion of Iraq because of weapons of mass destruction.
No chemical, biological or nuclear weapons programmes have ever been found. Amid widespread chaos in Iraq, Bush has insisted that the March 2003 invasion was still the right move.
Powell fought in Vietnam and rose to become a four star general and head of the Joint Chiefs of Staff from 1989 to 1993.
During the first Gulf War he pressed President George Bush senior not to overthrow Saddam, for fear of becoming bogged down in a protracted conflict.