Myers first began his professional ball playing career with the New York Mets in 1985 under the management of Davey Johnson.

Myers was an All-Star in 1990, 1994-1995, and 1997 and played in 2 World Series, winning one in 1986 with the New York Mets and in 1990 with the Cincinnati Reds. In a 14 year Major League career, Myers compiled a 3.19 ERA, 347 saves, 44 wins, 63 losses and struck out 884 batters in 884.2 innings. In 1993, Myers set the single season record for saves in the National League with 53 while playing with the Chicago Cubs. Randy Myers currently ranks 7th on the all-time Major League career saves list.

In 2000, Myers earned a salary of $6,916,667.00 while unable to pitch due to a damaged shoulder. Most of his 1999] and 2000 seasons were spent receiving treatment in the Padres training room after undergoing rotator cuff surgery in 1999; his injury resulted in a legal dispute between the Padres and their insurance carrier after the carrier denied an $8 million claim due to Myers' inability to play.

In October 1990, Myers was featured on the 18 ounce box of Wheaties breakfast cereal along with fellow Cincinnati Reds 1990 World Series champions Eric Davis, Jose Rijo, Barry Larkin, Chris Sabo and Hal Morris.

In 2004, his first year of eligibility, Myers received less than 5f the vote (he received 1 vote; the threshold was 25) from the Baseball Writers Association of America (BBWAA) for induction into the Baseball Hall of Fame, thus becoming ineligible to appear on future BBWAA ballots. However, he may eventually be considered for induction into the Hall by the Veterans Committee once 20 years have passed from his date of retirement (therefore, in the year 2019), in accordance with current Hall of Fame rules (enacted in 2001).