Throwing and batting right-handed, Harrelson played for four teams: the Kansas City Athletics (1963-66, 1967), Washington Senators (1966-67), Boston Red Sox (1967-69), and Cleveland Indians (1969-71). In his nine-season career, Harrelson was a .239 hitter with 131 home runs and 421 RBI in 900 games.

His time with the Athletics ended abruptly in 1967 when Harrelson angrily denounced team owner Charlie Finley following the dismissal of manager Alvin Dark. Saying that Finley was "a menace to baseball," Harrelson was released and ended up signing a lucrative deal with the Boston Red Sox, who were in contention to win their first pennant since 1946.

Brought in to replace the injured Tony Conigliaro, Harrelson helped the team win the pennant, but watched the team drop a close World Series to the St. Louis Cardinals in seven games. However, in 1968, he had his finest season, making the American League All-Star team and leading the American League in Runs Batted In with 109.

On April 19, 1969, Harrelson was traded to the Indians, a move that shocked him and led him to briefly retire. Following conversations with commissioner Bowie Kuhn and a contract adjustment by Cleveland, Harrelson reported to the team, finishing the year with 30 home runs. He also used his local celebrity to briefly host a half-hour program entitled, "The Hawk's Nest" on local CBS affiliate, WJW-TV.

During spring training the following year, Harrelson suffered a broken leg while sliding into second base during a March 19 exhibition game against the Oakland Athletics. The injury kept him on the sidelines for much of the season. When Indian rookie Chris Chambliss took control of the first base position in 1971, Harrelson decided to retire to pursue a professional golf career.

After his time on the links brought minimal compensation over the next few years, Harrelson turned to a broadcasting career, beginning in 1975 with the Red Sox. He then worked for a number of teams, including the Chicago White Sox in two separate stints, and was hired as general manager for the White Sox for one season in 1986. Since 1990, he has served as one of the team's announcers.

As the announcer for the White Sox, Harrelson is known for his distinctive home run call, "That ball hit deep. Waaaaaaaaaay back. He looks up, you can put it on the booooooooooooooaaaaaaard... YEEEEEEEEEEEEEES!" When a player on the opposing team strikes out, he goes into his famous call, "HE GONE!" Also if there is a ball that has a chance of being a home run he often yells "C'mon ball! Stretch! Stretch ball!"

Harrelson's distinctive announcing style is a subject of much contention amongst Chicago sports fans. Most have criticized him for the monotony of his voice, his repetitive and predictable and over the top calls, and his frequent long stretches of silence while calling a game, especially if the White Sox play on the field is subpar. Although popular with many White Sox fans, he has consistently been one of the most unpopular Baseball commentators nationwide due to perceived homerism.

Harrelson coined many nicknames for popular Sox players, including "Black Jack" McDowell, Carlos "El Caballo" Lee, and Frank "The Big Hurt" Thomas.