In 1956 Moss ran unsuccessfully for the Democratic nomination for governor. Two years later he ran for the U.S. Senate against two-term incumbent Arthur V. Watkins, who was a close ally of both the Eisenhower administration and the Mormon Church, and also against J. Bracken Lee, a non-Mormon and former two-term Utah governor (1949-57), who was running as an independent after losing to Watkins in the Republican primary. The Republican vote was split in the general election and Moss was elected with less than 40 percent of the vote.

Moss was elected to a second term in 1964, soundly defeating with 57 percent of the vote Brigham Young University President Ernest L. Wilkinson, a conservative Republican, in a bitter campaign. He was elected to a third term in 1970 when he won 56 percent of the vote against four-term congressman Lawrence Burton. The campaign was close until the final weeks, when a series of attempts by Burton misfired which had tried to paint Moss as an unpatriotic, closet liberal who supported reduced penalties for drug use and riots on college campuses.