He played in Major League Baseball (MLB) for the Atlanta Braves, Philadelphia Phillies, Cleveland Indians, Texas Rangers, Baltimore Orioles, Colorado Rockies and Seattle Mariners.

While with the Braves, Millwood was part of a pitching rotation which featured Greg Maddux, Tom Glavine and John Smoltz.

Millwood formed a part of the Braves' star pitching rotation, which also consisted of Greg Maddux, John Smoltz and Tom Glavine.

[4] In 1999, Millwood posted career-highs in wins (18, also achieved in 2002), earned run average (2.68), strikeouts (205) and WHIP (0.996).

Before the 2003 season, Millwood was traded by the Braves to the Philadelphia Phillies for catcher Johnny Estrada in order to cut their payroll in the midst of economic difficulties.

[10] Millwood was traded to the Baltimore Orioles on December 9, 2009, for Chris Ray and a player to be named later (left-handed pitcher Ben Snyder, a Rule 5 pick from San Francisco).

[16] He was called up from Triple-A and made his first major league start of the season on April 22 against the Chicago White Sox.

[20][21] On June 8, Millwood pitched the first six innings of a combined no-hitter against the Los Angeles Dodgers before leaving the game due to a groin injury.

[22] Charlie Furbush, Stephen Pryor, Lucas Luetge, Brandon League, and Tom Wilhelmsen helped him complete the bid.

Millwood was put on the disabled list in September with soreness in his shoulder and missed the remainder of the regular season.