He played sixteen seasons, from 1989 to 2004, for the St. Louis Cardinals, Chicago Cubs, Philadelphia Phillies, Baltimore Orioles, Los Angeles Dodgers, Florida Marlins, Texas Rangers, New York Mets, Colorado Rockies, New York Yankees, and Montreal Expos.

Cardinals manager Joe Torre wanted to make room for catcher Tom Pagnozzi and believed Zeile would be a more productive hitter and would have a longer career if he moved from behind the plate, so Zeile moved, with some reluctance, initially to first base and then to third base in 1990.

He batted .268 with 20 home runs and 80 RBI in 134 games with the Phillies in 1996 until he was acquired along with Pete Incaviglia by the Orioles on August 29 of that year in a transaction that was completed when Calvin Maduro and Garrett Stephenson were sent to Philadelphia on September 3 and 4 respectively.

In 2000, Zeile signed a contract with the New York Mets and moved to first base to replace John Olerud, and participated in the World Series that year.

Zeile's span is now the third longest, with Craig Biggio starting the penultimate game of his career at catcher in 2007 after not playing the position for 16 years.

In the 6th inning, in his final at-bat as a major leaguer, Zeile hit a three-run home run to left-field off Montreal Expos pitcher Claudio Vargas.

In the 8th inning, in his final play as a major leaguer, Ryan Church popped up to him, as a catcher, in foul territory.

Since retiring from Major League Baseball, Zeile has pursued two other passions: film production, and acting.

He founded Green Diamond Entertainment, a film production company in West Hollywood, California,[9][10] during his second stint with the Mets.

[13] Zeile attended William S. Hart High School in Santa Clarita, California, where he was an outstanding student-athlete.