Zimmer, nicknamed both "Zim" and "Popeye", began his career in 1949 at Cambridge of the (Maryland) Eastern Shore League. He then played in Hornell, New York, Elmira, New York, Mobile, Alabama, and finally St. Paul, Minnesota before making it to the major leagues with the Brooklyn Dodgers in 1954. Zimmer's rise to the major leagues was amazing considering he nearly died after being hit with a pitch while with St. Paul in 1953. He was beaned again in 1956 but he perservered.

In the major leagues, Zimmer remained with the Los Angeles Dodgers after their move west in 1958, then playing for the Chicago Cubs, the first New York Mets team in 1962, and the Cincinnati Reds; he returned briefly to the Dodgers in 1963, before finishing his career with the Washington Senators.

In 12 seasons, Don Zimmer played 1095 games. He compiled 773 hits, 91 home runs, 352 RBI, 45 stolen bases and a .235 batting average. He played in the World Series with the Dodgers in 1955 and 1959, and was selected to the National League All-Star team in 1961.

Although he had a low batting average, Zimmer was a fine infielder, willing to fill in at third base, shortstop, and second base. He also caught 33 games in his final season with Washington in 1965.

After his retirement, Zimmer managed in the minor leagues until 1971 when he joined the Montreal Expos. He was coaching the San Diego Padres when he was called on to replace Preston Gomez as manager. After being fired by the Padres, he coached and managed the Boston Red Sox, leading them into a one-game playoff with the New York Yankees for the 1978 American League Eastern Division title; the Yankees triumphed on a legendary home run by Bucky Dent over the Fenway Park Green Monster. Zimmer then managed the Texas Rangers, coached three stints with the Yankees, and coached and managed the Cubs leading them to the NL Eastern Division title in 1989 before returning to Boston.

Zimmer was on the first coaching staff of the expansion Colorado Rockies in 1993. In 1996, he joined the Yankees for their run of four World Series titles. Many fans know him for his "brawl" with Pedro Martinez in the 2003 American League Championship Series. Currently, Zimmer is a senior advisor for the Tampa Bay Devil Rays. His role includes assisting the team during spring training and during home games.

Overall, Zimmer won 906 major league games as a manager. With the Cubs, he was named Manager of the Year in 1989. He is the last former Brooklyn Dodger still serving on the field in some capacity.

He has written 2 books, Zim: A Baseball Life, and The Zen of Zim, that describe his life in baseball, as a player, manager, and coach.

On April 18, 2006, the Boston-based magazine Phoenix gave Zimmer the title of "29th unsexiest male celebrity".

He likes to brag that he had never drawn a paycheck outside of baseball.