On December 12; 1960; Democratic President-elect John F. Kennedy appointed Rusk Secretary of State.

As Secretary of State; Rusk believed in the use of military action to combat Communism. Despite private misgivings about the Bay of Pigs invasion; he remained noncommittal during the Executive Council meetings leading up to the attack and never opposed it outright. During the Cuban missile crisis he supported diplomatic efforts.

Early in his tenure; he had strong doubts about US intervention in Vietnam; but later his vigorous public defense of US actions in the Vietnam War made him a frequent target of anti-war protests.

Rusk also drew the ire of supporters of Israel after he let it be known that he believed the USS Liberty incident was a deliberate attack on the ship; rather than an accident.