Eric Milton's journey through Major League Baseball began when he was drafted by the New York Yankees in the first round of the 1996 MLB Draft. However, it was with the Minnesota Twins that he would first step onto the major league stage. Traded to the Twins in 1997, Milton made his MLB debut on April 5, 1998. As a left-handed pitcher, he quickly became a regular in the Twins' starting rotation.

Milton's early years with the Twins were marked by steady development. In 1999, he achieved a career highlight by pitching a no-hitter against the Anaheim Angels on September 11. This feat underscored his potential and placed him in the spotlight. Over the next few seasons, Milton continued to be a reliable starter for Minnesota, known for his ability to strike out batters and maintain composure on the mound.

The year 2001 was particularly noteworthy for Milton, as he was selected to the American League All-Star team. This recognition was a testament to his performance and consistency as a pitcher. During his tenure with the Twins, he helped the team reach the postseason in 2002, contributing to their success in the American League Central Division.

In 2003, Milton's career took a turn when he was traded to the Philadelphia Phillies. His time with the Phillies was marked by a solid 2004 season, where he recorded 14 wins. Despite his efforts, the team did not make the playoffs, and Milton became a free agent at the end of the season.

Milton signed with the Cincinnati Reds in 2005, a move that came with high expectations. However, his performance with the Reds was inconsistent, partly due to injuries that plagued his time there. Despite these challenges, Milton remained a part of the Reds' rotation until 2007, when he underwent Tommy John surgery, effectively ending his season.

After recovering from surgery, Milton attempted a comeback with the Los Angeles Dodgers in 2009. He made a few appearances with the team, but his time in the majors was limited. By the end of the 2009 season, Milton's professional playing career came to a close.