Moyer was selected a New York - Penn League All-Star in 1984. He made his major league debut on June 16, 1986 against the Philadelphia Phillies, and got his first win. Later that year on August 16, he threw his first shutout against the Montréal Expos.

In 1987, Moyer ranked 10th in the National League with 147 strikeouts while winning 10 games.Following his then statistically best season in 1988, Moyer was traded to the Texas Rangers.

Moyer was on the DL with a sore left shoulder for much of a disappointing 1989 season. 1990 saw Moyer spend time in the bullpen before regaining a spot in the starting rotation.

Moyer was released as a free agent after the 1990 season and was signed by the St. Louis Cardinals. He made seven starts for the Cardinals in 1991 before being sent to the minor leagues on May 24, and was released on October 14.

In 1992, Moyer went to spring training with the Chicago Cubs, but was released and spent the rest of the season in the minor league system of the Detroit Tigers. On December 8, 1992 Moyer signed with the Baltimore Orioles.

Moyer began the 1993 campaign in the Oriole minor leagues before being called up on May 30. He set a then career-high total in wins with 12 and a new career-low ERA of 3.43. Moyer regressed some in the strike-shortened 1994 season, but was third on the team in innings pitched. In 1995, Moyer again found himself in the Baltimore bullpen, but worked his way back into the starting rotation. He was released following the 1995 campaign, but his contract was picked up by the Boston Red Sox on December 22.

Moyer started the 1996 season in the Boston bullpen, but made seven starts for the Red Sox during the year. He was traded to the Seattle Mariners on July 30, where he would start 11 games and go 6-2. His combinded record of 13-3 would lead the majors in winning percentage at an .813 clip.

In 1997, Moyer enjoyed his best season to date. He was fifth in the American League with 17 wins and his 17-5 record gave him the second highest winning percentage (.773) in the league. Moyer would make his first postseason start against his former club Baltimore, but was forced out with a strained elbow in the fifth inning.

In 1998, Moyer went 15-9 with a 3.53 ERA. He was third in innings pitched with 234.1. He registered his 100th career win against the Cleveland Indians on August 27, as well as his 1000th career strikeout with a sixth inning whiff of David Bell. He was named Seattle's Pitcher of the Year by the Seattle chapter of the BBWAA.

In 1999, Moyer established himself as one of baseball's consistent pitchers. He went 14-8 with a 3.87 ERA. He was voted to The Sporting News AL All-Star team. He again won the Seattle Pitcher of the Year award.

2000 saw Moyer rebound from an early shoulder injury to nail 13 wins, giving him at least 13 in each of his past five seasons. He made his first Opening Day start for Seattle, but lost to the Boston Red Sox 2-0 on April 4. His shoulder problems led his ERA to balloon to 5.49 and a knee injury caused him to miss Seattle's trip to the American League Championship Series against the eventual World Series champion New York Yankees.

2001 was Jamie Moyer's best season to date and he played a major role in propelling the Mariners to a Major League record 116 wins. His 20 wins ranked tied for second in the American League, and his 3.43 ERA was sixth in the AL. On May 19, Moyer pitched one of the best games of his career against the New York Yankees, setting down 21 of the 22 batters he faced. He earned his 150th career win against the Texas Rangers on September 24. He became only the second Mariner in history to win 20 games on October 5, former teammate Randy Johnson being the other. Moyer went 3-0 with a 1.89 ERA in the postseason. He won Games 2 and 5 for the Mariners against the Cleveland Indians and also carried Game 3 against the New York Yankees before Seattle lost in Game 5.

In 2002 Moyer went 13-8 with a then career low 3.32 ERA. Moyer was often plagued by lack of run support in some of games, where although he pitched 20 more innings and had a lower ERA than in 2001, he won eight fewer games.

2003 saw the now forty year old Moyer come back to the mound and have his statistically best season. Moyer won a career high 21 games, cruised to a 21-7 record with a career low 3.27 ERA. He was tied for second in the American League for wins and was sixth in ERA. His .750 winning percentage placed him fourth in the league and his 21 wins are a club record. He became the only Seattle pitcher to win 20 games more than once. Moyer was voted to his first All-Star Game in 2003. He was named for the third time the Seattle Pitcher of the Year.

2004 saw Moyer's statistics slip, as well as the Seattle Mariners place atop the American League West. Moyer went 7-13 and posted his first losing record since 1994. While the year started well for him, going 5-0 with a 1.59 ERA from May 20 - June 18, Moyer ended 2004 on a 10-game losing streak. One positive for Moyer was he was awarded the Branch Rickey Award for his exceptional community service following the season.

The 2005 season was a major improvement for Moyer. He passed Randy Johnson to become the winningest pitcher for the Mariners on May 30. On June 8, 2005, Moyer became the 25th southpaw to win 200 games in the majors. He avoided a collapse similar to that from 2004 and finished with a 13-7 record.

Moyer currently lives in Seattle with his wife Karen (the daughter of former Notre Dame basketball coach and current sportscaster Digger Phelps) and their six children.

Moyer is best known for his methodical approach to the game and his devastating change-up. He reportedly keeps a log of all the batters he has faced in which he details their strengths and weaknesses.