In the 1968 presidential election, McCarthy was the first candidate to challenge incumbent Lyndon B. Johnson for the Democratic nomination for president of the United States, running on an anti-Vietnam War platform. The unexpected vote total he achieved in the New Hampshire primary led Johnson to withdraw from the race, and lured Robert F. Kennedy into the contest. McCarthy would unsuccessfully seek the presidency five times altogether.

The son of a deeply religious mother of German descent and strong-willed father of Irish descent who was a postmaster and cattle buyer known for his earthy wit, McCarthy grew up in Watkins, Minnesota, as one of four children and attended St. Anthony's Catholic School in Watkins. A bright student who spent hours reading his aunt's Harvard Classics, he was deeply influenced by the monks at nearby St. John's Abbey and University. McCarthy spent nine months as a novice before he left the monastery, causing a fellow novice to say, "It was like losing a 20-game winner."

McCarthy graduated from Saint John's Preparatory School (Collegeville, Minnesota) in 1931. He was a 1935 graduate of St. John's University in Collegeville, Minnesota. McCarthy earned his master's degree from the University of Minnesota in 1939. He taught in various public schools in Minnesota and North Dakota from 1935 to 1940, when he became a professor of economics and education at St. John's, working there from 1940 to 1943.

He was a civilian technical assistant in the Military Intelligence Division of the War Department in 1944 and an instructor in sociology and economics at the College of St. Thomas, St. Paul, Minnesota from 1946 to 1949.

McCarthy was a member of the Minnesota Democratic-Farmer-Labor Party. Representing Minnesota's Fourth Congressional District, McCarthy served as a member of the United States House of Representatives from 1949 to 1959. In 1958 he was elected to the U.S. Senate. He was a member of (among other committees) the powerful Senate Foreign Relations Committee.

He was introduced to a larger audience in 1960 when he supported twice-defeated candidate Adlai Stevenson for the nomination. He claimed during his speech "Do not reject this man who made us all proud to be called Democrats!" He was considered as Lyndon Johnson's running mate in 1964, only to have fellow Minnesota Senator Hubert Humphrey chosen for that position.[citation needed]

Along with Ted Kennedy, he was one of the original co-sponsors of the Immigration Act of 1965. He later regretted this, noting that "unrecognized by virtually all of the bill's supporters, were provisions which would eventually lead to unprecedented growth in numbers and the transfer of policy control from the elected representatives of the American people to individuals wishing to bring relatives to this country." Taking a turn to the right, McCarthy became a member of the Board of Advisors of the Federation for American Immigration Reform.

McCarthy met with Marxist revolutionary Che Guevara in New York City in 1964 to discuss repairing relations with the U.S. and Cuba. The two met in journalist Lisa Howard's Park Avenue apartment. This event is depicted in the film Che: Part One.

In 1968, McCarthy ran against incumbent President Lyndon Johnson in the New Hampshire Democratic primary, with the intention of influencing the federal government — then controlled by Democrats — to curtail its involvement in the Vietnam War. A number of anti-war college students and other activists from around the country traveled to New Hampshire to support McCarthy's campaign. Some anti-war students who had the long-haired appearance of hippies chose to cut their long hair and shave off their beards, in order to campaign for McCarthy door-to-door, a phenomenon that led to the informal slogan "Get clean for Gene."

McCarthy's decision to run was partly an outcome of opposition to the war by Wayne Morse of Oregon, one of the two Senators to vote against the Gulf of Tonkin Resolution. Morse gave speeches denouncing the war before it had entered the consciousness of most Americans. Following that, several politically active Oregon Democrats asked Robert Kennedy to run as an anti-war candidate. Initially Kennedy refused, so the group asked McCarthy to run, and he responded favorably.