Muste taught Latin and Greek at Northwestern Classical Academy (now Northwestern College) from 1905 to 1906. He was ordained a Dutch Reformed minister in 1909. In 1917, he resigned his ministry when his pacifism led to conflicts with his Dutch reformed parishioners. Muste volunteered for the American Civil Liberties Union and was enrolled as a minister of the Religious Society of Friends in 1918. He was active in labor affairs from 1919 and was general secretary of the Amalgamated Textile Workers of America from 1920 to 1921. He also taught at Brookwood Labor College from 1921 to 1933. He was the executive director of the Fellowship of Reconciliation from 1940 to 1953, during which time he became an advisor to Martin Luther King Jr.
Muste was sometimes affiliated with the Communist Party USA, though he later renounced communism and considered himself a “Calvinist socialist”. He was a supporter of Eugene V. Debs and Robert M. La Follette, Sr, and also had close friendships with John Dewey and Norman Thomas. In 1957, Muste headed a delegation of observers to the 16th. National Convention of the Communist Party. He was also on the national committee of the War Resisters League (WRL) and received their Peace Award in 1958. At the end of his life, Muste was active in the movement against the Vietnam War. In 1966, he traveled to Saigon in April and Hanoi in December. He was arrested and deported from South Vietnam, but received a warm welcome in North Vietnam from Ho Chi Minh.