He served in the management of the US State Department from 1961 to 1966 and is remembered by most as the only cabinet member of Presidents John F. Kennedy and Lyndon B. Johnson who was a major dissenter against the escalation of the Vietnam War.

Ball advised against deploying U.S. combat forces, as he believed it would lead the United States into an unwinnable war and result in a prolonged conflict.

He helped determine American policy regarding trade expansion, Congo, the Multilateral Force, de Gaulle's France, Israel and the rest of the Middle East, and the Iranian Revolution.

Ball likewise had a major role in Stevenson's 1956 presidential campaign and unsuccessful 1960 bid to gain the Democratic nomination.

"[4][note 1] In response to this prediction, the President seemed unwilling to discuss the matter, responding with an overtone of asperity: "George, you're just crazier than hell.

In a February 24, 1965, memorandum he passed to the President through his aide Bill Moyers, Ball provided an accurate analysis of the situation in South Vietnam, and of the U.S. stake in it, as well as a startlingly prescient description of the disaster any escalation of American involvement would entail.

Urging Johnson to re-examine all the assumptions inherent in the arguments for increasing U.S. involvement, Ball stood alone among the upper echelons of Johnson's policymakers when he attacked the prevailing notion, virtually unquestioned at the time in Washington, that America's fundamental strategic interest in escalating the conflict was in protecting U.S. international prestige and the reliability of its commitments to allies.

He observed that other international actors, including both allies and enemies, were concerned not whether the U.S. could live up to its promise but rather whether the U.S. could avert a disaster in time instead of squandering strategic capital in a struggle to assist a failed regime.

He "called for the recalibration of America’s Israel policy in a much noted Foreign Affairs essay" during 1977[9] and, during 1992, co-authored The Passionate Attachment with his son, Douglas Ball.

"[11][12][13] He often used the aphorism (perhaps originally invented by Ian Fleming in the novel Diamonds Are Forever) "Nothing propinks like propinquity," later dubbed the Ball Rule of Power.

Ball was an advocate of free trade, multinational corporations and their theoretical ability to neutralize what he considered to be "obsolete" nation states.