Lee Pil-mo began his acting career on stage before landing his first film role in the 1999 big-budget action film Shiri. In 2007, he appeared as one of the main characters in the KBS2 series Golden Age for Daughters-in-Law, which won him Best Supporting Actor at the KBS Drama Awards. In 2008, he became part of the hit KBS1 daily drama You’re My Destiny, which earned him an Excellence Award at the KBS Drama Awards. In 2009, he was nominated for another Excellence Award at the KBS Drama Awards for his performance in Sons of Sol Pharmacy House. In 2012, he starred in the high-rating MBC retro-drama Light and Shadow, which gave him an Excellence Award nomination at the MBC Drama Awards. In 2016, he was cast in the MBC family drama All’s Well With a Happy Home, which scored him acting trophies at that year’s APAN Star Awards and MBC Drama Awards.

In February 2019, Lee Pil-mo married interior designer Seo Soo-yeon, who he met on the TV Chosun dating show Taste of Love. Later that year, the couple became parents to a son.