Called up from the AAA Louisville Redbirds, he made his Major League debut with the Cardinals on June 17, 1983, collecting a double, a run batted in (RBI) and making three putouts in the outfield without an error.

During the 1991 Gulf War, when MLB decreed all players would wear both the Canadian and U.S. flags on their batting helmets as a patriotic gesture, Van Slyke scraped the Maple Leaf off his helmet, stating "I guess the people in Quebec won't be upset because the last time we were there they booed [the Canadian] National Anthem".

In 1988, Van Slyke set career highs with 25 home runs and 100 RBIs, led the majors with 15 triples and 13 sacrifice flies, and finished fourth in National League MVP voting.

Van Slyke played for four teams in his career: the St. Louis Cardinals (1983–1986), Pittsburgh Pirates (1987–1994), Baltimore Orioles (1995), and Philadelphia Phillies (1995).

[5] Prior to the 2006 season, Van Slyke was named first base coach for the Detroit Tigers by manager Jim Leyland, under whom he had played in Pittsburgh.

When Lloyd McClendon was named the Seattle Mariners' manager prior to the 2014 season, Van Slyke was hired to be the team's first base coach.

(with co-author Rob Rains), a book in the subgenre sports fiction about the Chicago Cubs finally breaking their one hundred year curse and playing in the World Series.

Van Slyke played baseball for the University of Kansas and for four seasons in the St. Louis Cardinals' minor league system.