Perkins was born in Hindman, Kentucky. He attended the Knott County, Kentucky grade schools, Hindman High School, Caney Junior College (now Alice Lloyd College), Lees Junior College and graduated from Jefferson School of Law (now the University of Louisville Law School) in 1935.

Perkins was admitted to the bar in 1935 and commenced the practice of law in Hindman. In 1939 Perkins served an unexpired term as Commonwealth's Attorney for the thirty-first judicial circuit. He was elected to the Kentucky House of Representatives in 1940 and was then elected Knott County Attorney in 1941 and reelected in 1945. Perkins resigned the county attorney's office on January 1, 1948 to become counsel for the Kentucky Department of Highways.

During World War II Perkins enlisted in the United States Army and saw service in Europe.

In 1948 Perkins ran against the incumbent Congressman from Kentucky's 7th District, Wendell H. Meade. Perkins unseated Meade and was elected as a Democrat to the Eighty-first and to the seventeen succeeding Congresses and served from January 3, 1949, until his death. Perkins was the chairman of the Committee on Education and Labor (Ninetieth through Ninety-eighth Congresses, 1967-1984). While a part of the committee, his work helped produce the Economic Opportunity Act of 1964 and Head Start.

Perkins was a resident of Hindman, Kentucky until his death on August 3, 1984 in Lexington, Kentucky. He is buried in the Perkins Cemetery at Leburn, Kentucky.

Perkins was succeeded in office by his son Carl C. Perkins. Both the Carl D. Perkins Bridge crossing the Ohio River and the Carl D. Perkins Federal Building and United States Courthouse in Ashland, Kentucky are named after him. The federal student loan called the Perkins Loan is named after Perkins.