In 1944, Myers was elected to the U.S. Senate after narrowly defeating Republican incumbent James Davis by 50%-49%. He was the first Catholic to serve as Senator from Pennsylvania. At the 1948 Democratic National Convention in Philadelphia, Myers served as chairman of the platform committee; in that position, he helped draft a party platform that strongly supported civil rights. He was Senate Majority Whip from 1949 to 1951, serving under Majority Leader Scott Lucas.