Over his 25-year career in Major League Baseball (MLB), Moyer pitched for the Chicago Cubs, Texas Rangers, St. Louis Cardinals, Baltimore Orioles, Boston Red Sox, Seattle Mariners, Philadelphia Phillies, and Colorado Rockies.

At the time of his final game, he was the oldest player in the major leagues and had the most wins, losses, and strikeouts of any active MLB pitcher.

He made his major league debut with the Cubs on June 16, 1986, against Steve Carlton and the Philadelphia Phillies, and earned his first win.

[9] Following his then-best season in 1988, the Cubs traded Moyer, Rafael Palmeiro, and Drew Hall to the Texas Rangers for Mitch Williams, Paul Kilgus, Curtis Wilkerson, Steve Wilson, Luis Benitez, and Pablo Delgado.

In 1992, Moyer attended 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.

In the middle of the 1996 season, Moyer was traded by the Red Sox to the Seattle Mariners on July 30, for outfielder Darren Bragg.

In the Division Series, Moyer made his first postseason start against his former club Baltimore, but was forced out with a strained elbow in the fifth inning.

Moyer's three shutouts were tied for fourth in the majors, and he was fifth in the American League in wins above replacement (WAR) for pitchers, per Baseball Reference.

He was tied for second in the league with 34 starts, fifth in opponents' batting average, holding opposing hitters to a .230 clip, and ninth in ERA with 3.32.

He was named the Seattle Pitcher of the Year for the third time and was also the recipient of the Roberto Clemente Award, given annually to a player whose success on the field is mirrored by his impact in community service.

Moyer also won the Hutch Award, presented annually by the Fred Hutchinson Cancer Research Center to an MLB player displaying "honor, courage and dedication to baseball, both on and off the field" and The Lou Gehrig Award, presented annually to the MLB player who both on and off the field best exemplifies the character of Lou Gehrig.

He finished with a 13–7 record, and for the second year in a row he threw the slowest fastball of all major league starters, averaging 81.7 mph.

On July 21, at age 44, Moyer combined with David Wells to set the record for the oldest match up of lefty starters (88 years, 307 days) in major league history.

On the final day of the season, with the Phillies and Mets tied at the top of the division with 88 wins, Moyer defeated the Washington Nationals, pitching 51⁄3 innings and surrendering five hits and no earned runs, while Tom Glavine, who at the time was also one of the oldest players in the major leagues, was crushed by the Marlins at Shea Stadium, surrendering seven runs in the first inning, hitting a batter with the bases loaded, and recording only a single out before being pulled.

On September 11, Moyer won his 14th game of the season against the Milwaukee Brewers, which began a seven-game win streak for the Phillies.

On October 25, Moyer made his first World Series start against the Tampa Bay Rays, pitching 61⁄3 innings, giving up three runs, and receiving a no-decision.

On December 15, 2008, Moyer signed a two-year, $16 million contract with the Phillies, keeping him with the club through the conclusion of the 2010 season.

On July 16, Moyer won his 255th career game, pitching a one-hitter through seven scoreless innings and passing Jack Morris for 41st on the all-time wins list.

[32] When asked about retiring after the expiration of his Phillies contract at the end of 2010, Moyer said, "You know, I'm going to leave that as an open-ended question because I don't know how to answer that.

"[33] After the retirement of Ken Griffey Jr. in early 2010, Moyer and Omar Vizquel were the last two active players in MLB who played in the 1980s.

[34] On May 7, Moyer became the oldest player in Major League Baseball history (47 years, 170 days) to pitch a shutout, blanking the Braves on two hits, striking out five batters and walking none.

On June 5, Moyer became the third MLB pitcher to win 100 games after turning 40 years old, defeating the San Diego Padres, 6–2, using just 98 pitches to accomplish the feat.

[37] The injury proved to be a sprain in his ulnar collateral ligament and a strain of his flexor pronator, which resulted in Moyer missing the remainder of the 2010 season.

[40] He had Tommy John surgery on December 1, 2010, in New York, to repair the ulnar collateral ligament in his elbow, in hopes to make a comeback in 2012.

[38] On January 18, 2012, Moyer, age 49, signed a minor-league contract (with an invitation to spring training) with the Colorado Rockies, a team that did not exist when he made his MLB debut in 1986.

[42] The March 30 NBC Nightly News reported that Moyer made the opening day roster for the Rockies, and would be the number-two starter in the rotation.

[44] Moyer became the oldest player in MLB history to record an RBI on May 16 when he singled in two runs in the fourth inning against the Arizona Diamondbacks.

Moyer signed a minor league deal with the Baltimore Orioles on June 6, two days after being released by the Rockies.

[51] On September 7, it was reported that Moyer was attempting a comeback as a knuckleball pitcher, having consulted with Charlie Hough and Tim Wakefield over the summer.

Moyer and Stairs joined in-game reporter Gregg Murphy and play-by-play voice Tom McCarthy.