Lee Jong-seok got his start in the entertainment world as a model before making his acting debut in the 2010 SBS series Prosecutor Princess. That same year, he was launched into fame with his supporting role in the hit SBS fantasy rom-com Secret Garden. In 2011, he joined the MBC sitcom High Kick: Counterattack of the Short Legs, which earned him nominations for Best Male Variety Performer and Most Popular Actor at the 48th Baeksang Arts Awards. In 2013, he acted alongside Lee Bo-young in the popular SBS drama I Hear Your Voice, which won him numerous acting trophies. This was followed by two more successful dramas in 2014, namely Doctor Stranger and Pinocchio. He was named Most Popular Actor at the 51st Baeksang Arts Awards for his work in the latter. In 2016, he was paired with Han Hyo-joo in MBC’s W–Two Worlds, which gave him the Daesang at the MBC Drama Awards. In 2017, he took home a Top Excellence Award at the SBS Drama Awards for While You Were Sleeping.

Lee Jong-seok served as a public service worker from March 2019 to January 2021 for his mandatory military service. He is close friends with his fellow model-turned-actor Kim Woo-bin.