Lee Jin-wook began his entertainment career as a model before landing a role in the 2004 short film My New Boyfriend. In 2006, he took home the New Star Award at the SBS Drama Awards for his work in Alone in Love and Smile Again. In 2008, he starred in the SBS series City of Glass, in which he was nominated for an Excellence Award at the SBS Drama Awards. In 2013, he headlined the tvN time-travel drama Nine: Nine Time Travels, which earned him a Daesang nomination at the 6th Korea Drama Awards. In 2015, he was paired with Ha Ji-won in the SBS romance series The Time I’ve Loved You, which was adapted from the Taiwanese drama In Time With You. He was nominated for a Top Excellence Award at the SBS Drama Awards for his work in the series. In 2016, he was selected as one of the recipients of the Daesang at the Korea Movie Star Awards for the film Time Renegades. In 2018, he played a hot-tempered detective in the SBS series Return, which scored him a Top Excellence Award nomination at the SBS Drama Awards.

Lee Jin-wook enlisted for his mandatory military service in May 2009 and was discharged in March 2011. In April 2011, it was confirmed that he and his Air City co-star Choi Ji-woo ended their three-year relationship. In 2014, he briefly dated actress Gong Hyo-jin.