Mussina, nicknamed "Moose," graduated from Stanford University in December, 1990, earning a degree in economics in just 3 1/2 years. He was drafted by the Baltimore Orioles in the 1st round (20th pick overall) of the 1990 amateur draft and in 1992, his first full season with the Orioles, went 18-5 with a 2.54 ERA. Mussina continued to post good numbers in Baltimore, featuring two back-to-back 19-win seasons in 1995 and 1996. Mussina helped the Orioles to the playoffs in 1996, where they eventually lost in the ALCS to the Yankees and again in 1997, where they lost in the ALCS to the Cleveland Indians. In Game 3 of that series against Cleveland, Mussina set the ALCS record for strikeouts in a single game when he struck out fifteen Indians. (The record was later tied by the New York Yankees' Roger Clemens in Game 4 of the 2000 ALCS against the Seattle Mariners.)

Following the 2000 season, Mussina decided to leave the Orioles. Mussina signed with the New York Yankees on November 30, 2000 to a 6-year contract. Many Orioles fans saw the move as a failure to act on their hometown team's part. Many fans felt that Orioles management wrongly assumed Mussina would stay loyal to the team, despite being offered more money and being heavily courted by Yankees management. Contrary to popular belief, it was the Orioles' refusal to include a "No Trade Clause" in his contract, rather than money, that forced a change in teams.

Mussina pitched well in his first season, posting a 17-11 record with a 3.15 ERA. In the postseason, Mussina started Games 1 and 5 of the 2001 World Series against the Arizona Diamondbacks. In the 2001 postseason, Mussina posted a 2.63 ERA.

In 2002, Mussina finished 18-10 with a 4.05 ERA. In 2003, Mussina was 17-8 with a 3.40 ERA. In 2004, after high-profile defections by Roger Clemens, Andy Pettitte and David Wells, Mussina became the unquestionable "ace" of the Yankee pitching rotation. Mussina was plagued by a series of injuries, and wasn't the pitcher he was in 2003 or before. He finished the 2004 season, 12-9 with a 4.59 ERA with a great late-season performance. In 2005, Mussina wasn't the Yankees' ace anymore. He still was inconsistent throughout the season and finished 13-8 with a 4.41 ERA.

Mussina is having a great start to the 2006 season, posting a 2.67 ERA and a 8-1 record through his first 13 starts (as of June 6, 2006). Additionally, Mussina is among the AL leaders in virtually every pitching category including, T-1st in wins (8), 2nd in ERA (2.67), 3rd in Strike Outs (78), 1st in innings pitched (87.2), 3rd in WHIP (1.00), and 3rd in BAA (.221).