A five-time All-Star and seven-time Gold Glove winner, Mussina's consistency resulted in six top-five finishes in the voting for his league's Cy Young Award.

[8][9] Mussina was drafted by the Baltimore Orioles in 1987 but chose to attend college at Stanford University rather than sign.

His junior year in 1990 was his best, finishing 14–5 with a 3.50 ERA over 149 innings, before being drafted again by the Baltimore Orioles, this time as a first round pick (20th overall).

[11] Mussina made his professional debut with the Class AA Hagerstown Suns of the Eastern League in 1990.

He finished fourth in the American League Cy Young Award voting, and pitched one perfect inning in the 1992 All-Star Game.

Mussina struggled in 1993 due to shoulder soreness, which placed him on the disabled list (DL) from July 22 to August 19.

[15] Orioles fans believed Mussina was warming up in preparation to come in and pitch the ninth inning, and when Gaston put Duane Ward in to pitch the ninth inning, the fans at Camden Yards spent the rest of the game chanting "We Want Mike" and booing Gaston very loudly, as the popular slogan "Cito Sucks" was born in Baltimore.

Gaston was never treated well by Baltimore fans for the rest of his managerial career and he was subject to death threats for not pitching Mussina in the game.

[15] Mussina returned from the DL in August against the Texas Rangers,[14] only to have the Orioles shut him down three weeks later in mid-September due to lower back pain.

Mussina returned to form in 1994, but a player's strike cut his season short, causing him to finish with only 16 wins and 99 strikeouts in 176.1 innings of work.

He was selected to his third consecutive All-Star Game and pitched one inning, giving up one hit while striking out one batter.

Mussina finished fourth in voting for that year's American League Cy Young Award.

Despite his excellent season, Mussina was not elected to that year's All-Star Game, and finished fifth in the American League Cy Young Award voting.

He finished sixth in the American League Cy Young Award voting and won his second consecutive Gold Glove.

In the 1997 American League Championship Series he pitched 15 innings over two starts, allowing one run and four hits, and striking out 25—an ALCS record at the time.

Mussina's 1998 season was punctuated by two separate trips to the DL, including for injury resultant from when a ball hit by Sandy Alomar Jr. struck him on the face and fractured his nose.

Mussina won his third consecutive Gold Glove with a perfect 1.000 fielding percentage out of 50 total chances.

Mussina finished second in the American League Cy Young Award voting that year behind Pedro Martínez.

He committed just one error out of 61 total chances and won his fourth consecutive Gold Glove, further cementing his reputation as one of the top defensive pitchers in baseball.

[23] Mussina started Games 1 and 5 of the 2001 World Series against the Arizona Diamondbacks, posting an 0–1 record with a 4.09 ERA in 11 innings pitched.

On November 20, 2006, Mussina and the Yankees reached a preliminary agreement, pending a physical, on a two-year, $23 million contract.

[28] However, with the Yankees locked in a tight pennant race, Mussina struggled and temporarily lost his spot in the rotation to prospect Ian Kennedy.

After just one relief appearance, (the first of his regular season career), Mussina returned as a starter, going 3–0 in his final four starts to end with 11–10 record and a career-high 5.15 ERA.

Owner Hank Steinbrenner suggested that Mussina should "learn how to pitch like Jamie Moyer", and no longer rely so much on his fastball.

[29] Although that remark was widely interpreted as a slight, Mussina joked in response that he could not pitch like Moyer because he did not throw left-handed, and afterwards he excelled, going 9–1 in his subsequent 11 starts.

[33] Mussina would later finish second to Cleveland Indians pitcher Cliff Lee in the voting for American League comeback player of the year honors.

His finest postseason occurred in 1997 for the Orioles, when in four games he went 2–0 with a 1.24 ERA in 29 innings pitched while allowing 11 hits, four earned runs, seven walks and 41 strikeouts.

[43] A feature on The Washington Post's website ranked his performance the sixth-most memorable moment at Camden Yards.

During spring training in 2006, Yankees catcher Jorge Posada noticed the unique grip Mussina used for his changeup and promptly hit a home run off it during an intra-squad game.

The only other pitchers to match Mussina's 17 seasons of 10 or more victories are Ted Lyons, Tom Glavine, Gaylord Perry, Phil Niekro, Walter Johnson, Greg Maddux, Warren Spahn, Cy Young, Don Sutton, Tom Seaver, Tommy John and Steve Carlton; all are Hall of Famers, except Tommy John.