Duren was born in Cazenovia, Wisconsin. He was known for his fastball pitching, but also noted for his very poor vision and thick glasses. He was rumored to have hit a player waiting in the on-deck circle, supposedly because he could not see which way to throw to home plate.

He was originally signed by the St. Louis Browns (now the Baltimore Orioles) as a free agent before the 1949 season. His first major league game was on September 25, 1954 (by which time the Browns had moved to Baltimore). That was the only game he ever played for the Orioles; he wore uniform number 21.

On September 21, 1956 he was traded to the Kansas City Athletics as part of a trade involving three other players (Jim Pisoni and Duren went to the A's in exchange for Al Pilarcik and Art Ceccarelli). Kansas City assigned him uniform number 26.

The Athletics and Yankees did a lot of trading in that era, and on June 15, 1957 Duren, Pisoni, and Harry Simpson were traded to the Yankees for Billy Martin, Ralph Terry, Woodie Held, and Bob Martyn. Duren kept his A's uniform number of 26 on the Yankees. Duren's best year in terms of winning percentage was 1958, when he won 6 and lost 4 for the Yankees; and he received the first of his 3 All-Star selections as well. He has also been retroactively credited with saving 20 games in 1958, the high mark in the American League that year. In 1959, his won-lost record was much poorer, but his earned run average of 1.88 was the best of his career.

Duren stayed with the Yankees until May 8, 1961, when he was traded to the Los Angeles Angels; Duren, Johnny James, and Lee Thomas went to the Angels in exchange for Tex Clevenger and Bob Cerv. With the Angels Duren wore uniform number 30. Shortly after being traded to the Angels, he struck out seven successive Red Sox batters, an American League record.

The Philadelphia Phillies purchased Duren's contract from the Angels on March 14, 1963, and assigned him uniform number 18.

The Cincinnati Reds purchased Duren's contract from the Phillies on May 13, 1964. Duren wore two different uniform numbers (33 and 53) in his short Cincinnati career.

On April 13, 1965, the Reds released Duren to free agent status. That same day he was signed by the Phillies and given uniform number 30 (not his old Phillies number, but the number he had worn with the Angels). Duren was released to free agent status again by the Phillies on June 8. He was immediately signed by the Washington Senators and assigned uniform number 17, but was released again on August 24 to bring a close to his 10-year ML career.

In 1983, Duren was presented with the Yankee Family Award for his conquering alcoholism, and for service as an alcohol abuse educator.

Baseball Hall of Famer Ryne Sandberg was named in honor of Duren.