Milton was selected by the New York Yankees in the 1st round (20th pick) of the 1996 amateur draft, and was among four players traded to the Minnesota Twins two years later in exchange for Chuck Knoblauch. On September 11, 1999, he pitched a 7-0 no-hitter against the Anaheim Angels, the fifth no-hitter in Twins history. He is the only person to pitch a no-hitter in Major League Baseball and also for the Falmouth Commodores of the Cape Cod Baseball League.

With Minnesota, Milton had a record of 57-51, with 715 strikeouts and a 4.76 earned run average, and was selected to the 2001 AL All-Star team. He went 1-0 with a 1.65 ERA with the Twins in the 2002 and 2003 playoffs, and was traded to the Philadelphia Phillies for the pitcher Carlos Silva following the 2003 season.

Milton led the Phillies in wins, starts and strikeouts in 2004, going 14-6 with a 4.75 ERA and 171 strikeouts in 34 starts. Against the Chicago Cubs at Citizens Bank Park on July 25, Milton carried a no-hitter into the ninth inning, only to have Michael Barrett break it up with a leadoff double. The no-hitter would have been the first against the Cubs since Sandy Koufax's perfect game in 1965; Milton would also have become the sixth pitcher to pitch no-hitters in both leagues, joining Cy Young, Jim Bunning, Nolan Ryan, Hideo Nomo and, on May 18 of just that 2004 season, Randy Johnson.

At the end of the 2004 season, he signed as a free agent with Cincinnati and is on pace to earn an amazing $5.2 million per win.

In a seven-year career, Milton has compiled a 71-57 record with 876 strikeouts and a 4.76 ERA in 1188.1 innings pitched. Eric Milton has struggled with the Cincinnati Reds, with his easy to hit hanging curveball and weak fastball. Allowing many home runs.

Milton attended the University of Maryland, College Park.