Zeile broke into the majors in 1989 as a catcher and the Cardinals’ most anticipated prospect of the year. 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.

Zeile spent most of the 1990s as a third baseman. He was traded from the Los Angeles Dodgers to the Florida Marlins along with Mike Piazza in 1998 for five players, then was traded to the Rangers later that season. In 1999, Zeile was part of a historic Rangers team. Along with Gregg Zaun and Jeff Zimmerman, he was one of three players on the team whose last names began with “Z”. Not since the 1916 Chicago Cubs, with Heinie Zimmerman, Dutch Zwilling, and Rollie Zeider, had this occurred. Zeile ended the decade having committed more errors than any other player during the 1990s.

In 2000, he then signed a contract with the New York Mets, where he rejoined Piazza, and moved to first base for the Mets in 2000, who wanted him to replace John Olerud. In 2002, he was traded to the Rockies, where he moved back to third base. He led all National League third basemen in errors in 2002, with 21, when he had the lowest fielding percentage in the league (.942).

After one season with Colorado, Zeile became a free agent again and signed with the Yankees in 2003. He was released mid-August and was signed by Montreal three days later. Having decided 2004 would be his last season, Zeile returned to the New York Mets. He also voiced displeasure with the Yankees, saying that he has “no desire to play again for that organization”, and that “I think some of the things that happen over there are different than any other organization in baseball. I have a pretty good track record to judge that.”

Zeile retired following the 2004 season. Having planned his retirement in advance (and with the Mets well out of the playoff race), Mets manager Art Howe let Zeile once again start as a catcher, his original position, on September 18, 2004. It was Zeile’s first appearance there in 14 years. It was the second-longest span ever between appearances at the position. Gabby Street caught a game in 1931 after last having caught in 1912. Zeile’s span is now the third longest, since Craig Biggio started the final game of his career at catcher after a 16-year span.

Zeile got one final start as a catcher two weeks later on October 3, 2004 in the season’s final game, as the Mets’ regular catcher, Jason Phillips’s foot hurt him and he could not play. 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. It was also John Franco’s last out made as a Met pitcher. The Mets won the game, 8-1. Both games Zeile caught in his final season were started by Tom Glavine.

He also pitched an inning with the Mets when they didn’t have any pitchers left, as he gave up 5 runs in the 8th inning in the Mets’ 19-10 loss to Montreal on July 26, 2004. It was his second appearance as a pitcher, having also appeared in a game for the Rockies in 2002.

On October 3, 2004, he became one of 41 players (as of 2011) ever to hit a home run in his final at bat. Zeile’s final home run also made him the last person ever to hit a home run off a Montreal Expos pitcher. Following that game, which was the last of the season, the Expos moved to Washington, D.C. and became the Washington Nationals.

Zeile was married to Olympic champion Julianne McNamara, the first American gymnast to earn a perfect 10.0 at the Olympics. They have four children, including son Garrett (b. November 27, 1993), and daughter Hannah (b. November 7, 1997), the latter who has Type 1 diabetes. As a result, Zeile and McNamara have been particularly active in juvenile diabetes research charities. They divorced in January 2015. Their daughter, Hannah, appears on the TV series This is Us as teenager Kate Pearson.

On June 27, 2020, Zeile married Kristin Gamboa, daughter of ex-major league coach and minor league manager Tom Gamboa.