Cooper resigned his judgeship in November 1946 to seek the U.S. Senate seat vacated when A. B. "Happy" Chandler resigned to accept the position of Commissioner of Baseball. Cooper's opponent, former Congressman and Speaker of the Kentucky House of Representatives John Y. Brown, Sr., was better known and widely believed to be the favorite in the race. However, Brown had alienated Chandler's supporters in the Democratic Party during a hotly contested senatorial primary between Brown and Chandler in 1942, and this group worked against his election in 1946. Further, the "Louisville Courier-Journal" opposed Brown because of his attacks on former Senator J. C. W. Beckham and Judge Robert Worth Bingham, who were heads of a powerful political machine in Louisville. With these two factors working against Brown, Cooper won the election to fill Chandler's unexpired term by 41,823 votes, the largest victory margin by any Republican for any office in Kentucky up to that time. His victory marked only the third time in Kentucky's history that a Republican had been popularly elected to the Senate. The move to Washington, D.C. proved to be too much for Cooper's already strained marriage. In 1947, he filed for divorce, charging abandonment.