Zisk was drafted by the Pittsburgh Pirates out of Seton Hall University in the third round of the 1967 Major League Baseball draft. He made his major league debut on September 8, 1971, replacing Roberto Clemente in right field in the eighth inning of Pittsburgh’s 10–1 victory over the Chicago Cubs, and got a single in his first major league at-bat. Zisk also made seventeen appearances with the 1972 Pirates, however, he was not on either team’s post-season roster.

In Zisk’s rookie season, 1973, he batted .324 with ten home runs. On June 9, 1974, he hit for the cycle in a 14–1 victory over the San Francisco Giants at Candlestick Park. For the season, he led the Pirates with 100 runs batted in while also clubbing seventeen home runs. He made his only post-season appearances with the 1974 and 1975 Pirates. While batting an impressive .400 in the post-season, Zisk only scored one run and had no RBIs as the Pirates lost in five games to the Dodgers in the 1974 NLCS and were swept by the Reds in the 1975 NLCS. Following the 1976 season, the Pirates traded Zisk along with Silvio Martinez to the Chicago White Sox for Terry Forster and Rich Gossage.

His best season was in 1977, his lone year with the White Sox, when he hit 30 home runs and had 101 RBIs in addition to a .290 batting average. He started in left field for the American League in the 1977 All-Star game. He went two for three with a double and two RBIs.

In 2004, Richie Zisk was inducted into the National Polish-American Sports Hall of Fame.

Zisk played baseball at Parsippany High School. The Daytona Cubs retired Richie’s number 22 on July 20, 2007, with his family in attendance and on his bobblehead day. His younger brother, John, played a season in the Texas Rangers’ organization, and two for the independent Wausau Timbers of the Midwest League.

During 2011 and 2012, Zisk was in charge of pro scouting in Florida for the Chicago Cubs.