[2] He served until 1917,[2] when he resigned in order to join the United States Army for World War I.

He later rejoined the Missouri National Guard in 1921 as a major, serving on the staff of the adjutant general until 1928.

[5] In the 1920s he researched and authored a biography of John Quincy Adams,[7] and was active in politics as a campaign speaker for Democratic candidates in Missouri.

[8][9] In 1928 he considered running for the United States Senate seat of the retiring James A. Reed, but decided not to make the race.

[11] In the 1932 election, Clark ran for the United States Senate seat held by the retiring Harry B. Hawes,[12] and relied on his base among veterans to defeat two other candidates for the Democratic nomination.

[12] Hawes resigned on February 3, 1933, a month before his term was to end, and Clark was appointed to fill the vacancy, gaining seniority on other senators elected in 1932.

[12] In fall of 1937, Clark displayed a poster on the wall of the Senate chamber that included two images of the dead bodies of Roosevelt Townes and Robert McDaniels, victims of a lynching in Duck Hill, Mississippi in April.

The poster read, "These blow torch lynchings occurred while the Wagner-Van Nuys Anti-Lynching Bill was Pending before Congress.

[12] In April 1943, a confidential analysis of the Senate Foreign Relations Committee (of which Clark was a member) by British scholar Isaiah Berlin for the British Foreign Office succinctly characterized Clark as: a rabid isolationist and member of the American First Committee who has steadily voted against all the foreign policies and war measures of the Administration with the exception of the reciprocal trade agreements (in which the corn exporters of Missouri have some interest).

In testimony before the United States Senate, Rear Admiral Randall Jacobs strongly opposed the provision to include Veterans with blue discharges on the grounds that it would undermine morale and remove any incentive to maintain a good service record.

Senator Clark, a sponsor (writer) of the GI Bill, dismissed his concerns, calling them "some of the most stupid, short-sighted objections which could be raised".

[11] The ceremony took place at the Berryville, Virginia home of Clark's sister,[3] and President Truman served as best man.

[11] Clark and other isolationist senators are referenced in the Woody Guthrie song Mister Charlie Lindbergh.

[18] Guthrie's 1943 lyrics condemn pre-World War II isolationism and advocate for leaders committed to defeating fascism.