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, moving to first base for the Mets in 2000, who wanted him to replace John Olerud.

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 had this occurred (Heinie Zimmerman, Dutch Zwilling, and Rollie Zeider).

Zeile retired following the 2004 season. Having planned his retirement in advance, the Mets had him start one final game as a catcher - his first appearance there in 14 years - in September 2004. 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 hit at least one home run for each of the 11 teams he played for over the course of his career, distinguishing him as the one player in Major League history to have hit a home run for 10 or more teams. He is also one of 41 players ever to hit a home run in his final at-bat, which he did on October 3, 2004 as a New York Met.

Zeile is married to Olympic champion, Julianne McNamara, the first American gymnast to earn a perfect 10.0 at the Olympics. They have four children. He attended William S. Hart High School in Newhall, California, where he was an outstanding student and athlete. Todd is a decedent of John Adams, the second President of the United States. Since retiring from Major League Baseball, Zeile has pursued another passion, starting a film production company in California.