In 2001, Kim Bo-suk debuted as a rapper in the five-member boy band LEO. However, the band disbanded only after eight months. He then adopted the stage name Kim Ji-suk to avoid being confused with veteran actors Jung Bo-suk and Kim Bo-sung. He made his acting debut in the 2004 music video of Kim Hyun-joong for She’s Laughing. He was named Best New Actor at the 2007 KBS Drama Awards for the daily drama Likeable or Not. The 2009 hit movie Take Off propelled him to popularity. In 2016, Kim Ji-suk received various acting citations for his role in the 2016 tvN romantic comedy series Another Oh Hae-young. He also took home a Top Excellence Award at the 2017 MBC Drama Awards for the series 20th Century Boy and Girl. In 2019, he was cast in the KBS2 romantic comedy thriller When the Camellia Blooms, in which he earned an Excellence Award at the 2019 KBS Drama Awards.

Aside from his native Korean, Kim Ji-suk can also speak English and German. He has an older brother, who boasts an IQ of 150. He enlisted for his mandatory military service on May 24, 2010. He was discharged in March 2012 after serving an active duty with the Defense Media Agency of the Ministry of National Defense. He is close friends with actresses Yoo In-young and Jung Yumi.