He was a U.S. Senator for two terms from January 3, 1967 to January 3, 1979. In 1967 he served on the President's Commission on Civil Disorders. He was a member of the liberal wing of the Republican Party, and often had conflicts with President Richard Nixon, particularly in 1970 when Brooke helped lead the movement to stop the Senate confirmation of the President's nominee to the Supreme Court, Harold Carswell. Brooke was re-elected in 1972, defeating Democrat John Droney 62%-34%. However, he lost much of his popularity during his second term after a contentious and widely publicized divorce. He lost a bid for a third term in 1978 to DemocraticRepresentativePaul Tsongas 55%-45%. After leaving the Senate, he was a member of the Low Income Housing Commission.
In September 2002, he was diagnosed with breast cancer and since then, has assumed a national role in raising awareness of the disease among men.