Upon graduation from Hanyang University in 1982, Lee made an agreement with the Korea Baseball Organization to play for one of the new pro league’s teams instead of remaining in the amateur league. Prior to the inaugural Korean professional baseball season, Lee was finally signed by the Samsung Lions. In the first game of the KBO pro league on March 27, 1982, Lee hit the first home run in Korean professional baseball history against the MBC Chungyong. Lee was a regular catcher of the Lions during the 1982 season and helped his team to reach to the inaugural Korean Series, where the Lions lost to the OB Bears, 4–1–1.
Lee Man-soo's number 22 was retired by the Samsung Lions in 2003.
Lee, nicknamed “Hulk” and "Babe Ruth of Korea" for his power and home run ability, was a full-time catcher for 16 seasons with the Samsung Lions, hitting 252 home runs and knocking in 861 RBIs during his career. In 1983, he won hist first home run title and was named League MVP, and the next year became the league’s first triple crown winner as the leader in three major offensive categories ― home runs (23), runs batted in (80) and batting average (.340). His Home Run and RBI totals also led the league in 1985. Gold Gloves came in 5 straight years, 1983–1987, and he appeared in 12 All-Star games. Lee's ultimate career home run total, 252, remained the record until Jang Jong-Hoon of the Hanwha Eagles hit his 253rd on May 23, 1999.
After the 2006 season, Lee returned to South Korea and signed a two-year contract with the SK Wyverns as the club's bench coach on October 30, 2006. On August 18, 2011, SK Wyverns manager Kim Sung-keun was sacked following his decision to retire from coaching after the 2011 season. Kim’s dismissal came just one day after the 68-year-old manager announced his decision to step down from his post at the end of the season, and Lee was named interim manager of the Wyverns on the same day.