In his major league career, he played for the New York Yankees from 1995–2003. He then signed with the Houston Astros, and played for them from 2004 through 2006. In 2007, Pettitte rejoined the Yankees. He has won five championships with the New York Yankees and is Major League Baseball's all-time postseason wins leader with 18.[citation needed]

Through 2009, Pettitte is 9th among active major league players in win-loss percentage (.629); 4th in wins (229); and 7th in strikeouts (2,150). He is also one of only two active players with at least 200 wins, 2,000 strikeouts, and a winning percentage at or above .600. The other, Pedro Martínez has not pitched yet in the 2010 season. In addition, he has secured the most wins of any pitcher during the 2000s.

Through 2009, Pettitte is 9th among active major league players in win-loss percentage (.629); 4th in wins (229); and 7th in strikeouts (2,150). He is also one of only two active players with at least 200 wins, 2,000 strikeouts, and a winning percentage at or above .600. The other, Pedro Martínez has not pitched yet in the 2010 season. In addition, he has secured the most wins of any pitcher during the 2000s.

Pettitte is of Italian and French descent, the younger of two children born to Tommy and JoAnn Pettitte. He attended Deer Park High School in Deer Park, Texas. Andy Pettitte also pitched the Deer to within one win of the state title. It was there he met his future wife Laura. Together, they have four children: Joshua Blake (born November 3, 1994), Jared (May 28, 1998), Lexy Grace (January 10, 2001), and Luke Jackson (June 20, 2005).

Selected by the Yankees in the 22nd round of the 1990 MLB draft, he opted instead to attend San Jacinto College North in Houston, Texas, where he won 8 of 10 decisions.

On May 25, 1991, he signed with the Yankees as an amateur draft and follow selection.

In his minor league career he went 51–22, with a 2.49 ERA in 113 starts. He never had a losing season. In the rookie league, he had an 0.98 ERA.

Pettitte made his major league debut on April 29, 1995, with the New York Yankees. In 1996, he made the American League All-Star team and finished second to Pat Hentgen for the AL Cy Young Award. He led the league in wins (21), was 3rd in W-L pct. (.724), and was 8th in the AL in ERA (3.87). The Yankees won the 1996 World Series with Pettitte going 1-1 in the 6 game series; in Game 1, he was hit hard early and did not last through the third inning, but he fared much better in Game 5, outdueling John Smoltz in a game that the Yankees won 1-0. The next year, Pettitte led the league in starts (35), pickoffs (14), and double plays induced (36), and was 3rd in the league in innings (240.3; a career high), 4th in ERA (2.88), wins (18), and W-L pct. (.720), 6th in complete games (4), 8th in strikeouts (166), and 10th in walks/9 IP (2.43). In 1998, he was 7th in the league in complete games (5; a career high), and 8th in wins (16). That season, he won his second World Series Title with the Yankees, winning his only start in the four game series.

The Yankees continued their success in 2000. New York won the AL East Pennant by 4 games while Pettitte was 3rd in the American League in wins (19), 6th in W-L pct. (.679), and 7th in complete games (3). He finished off the season with his fourth World Series Title. In 2001, he made the All-Star team for the second time and was named the MVP of the ALCS, after winning Games 1 and 5 against the Seattle Mariners. He was 3rd in the AL in walks/9 IP (1.84), and 8th in strikeouts (164) and strikeouts/9 IP (7.36).

The following year, he was 9th in the AL in W-L pct. (.722) and complete games (3). Pettite continued his success through 2003. Pettitte was 2nd in the league in wins (21), 5th in W-L pct. (.724), 6th in strikeouts (180; a career high) and strikeouts/9 IP (7.78; a career-best), 8th in games started (33), and 9th in walks/9 IP (2.16).

After the 2003 season, Pettitte left the Yankees, signing a 3-year, $31.5 million contract with the Houston Astros. He switched his uniform number to #21, in honor of Roger Clemens, who previously wore that number in Boston and Toronto. His 2004 season, in which he held batters to a .226 batting average, was shortened by elbow surgery.

Pettitte returned to form in 2005 to help the Astros make their first trip to the World Series. His 2.39 ERA in 2005 was a career-best, and 2nd-best in the National League behind teammate Roger Clemens. He was also 2nd in the league walks/9 IP (1.66) and LOB percentage (79.7%; a career best), 3rd in sacrifice hits (15), 5th in wins (17), and 8th in W-L pct. (.654). He held lefties, who over his career have outhit righties when batting against him, to a .200 batting average, had a career-best 4.17 SO/BB ratio.