Lee began his entertainment career as a model in 2007. He made his acting debut in the 2008 sitcom Here He Comes, followed by High Kick Through the Roof.
Lee's popularity increased after joining SBS's Good Sunday variety show Running Man, gaining the nickname "Prince of Asia" due to his large number of overseas fans. In 2010 and 2011, Lee won back-to-back awards at the SBS Entertainment Awards for "New Star Award" and "Best Newcomer in Variety" respectively.
In 2012, Lee played supporting roles in the romantic comedies Wonderful Radio and All About My Wife, and thriller The Scent. Later in the year, he reunited onscreen with his former Running Man co-star and real-life best friend Song Joong-ki in the TV melodrama The Innocent Man.
In 2013, after another supporting role in A Wonderful Moment, Lee voiced the lead character Marco in the animated movie Maritime Police Marco, opposite fellow Running Man regular Song Ji-hyo as the voice of Lulu.
Lee had publicly stated that he wanted to play as an antagonist in TV or film, and he got his wish when he was cast as Prince Imhae (villainous brother to King Gwanghae) in the 2013 period drama Goddess of Fire. While filming Goddess of Fire, he participated in an energy conservation campaign alongside child actress Kim Yoo-bin.
On 17 August 2013, Lee held his first ever solo fan meeting of his career in Singapore. Attended by 2,000 fans, it was considered a success. He held another one in Malaysia on 4 January 2014, attended by almost 3,000 fans.
In 2014, Lee played his first major role on the big screen in Confession. The neo-noir film is about three friends (played by Ji Sung, Ju Ji-hoon and Lee) whose friendship gets destroyed after getting involved in a murder case. He then returned to television with the medical melodrama It's Okay, That's Love, playing a patient suffering from Tourette syndrome, a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalizations called tics. Lee and Hwang Chansung (of boyband 2PM) then starred in the film A Dynamite Family, about five bickering brothers living in the village of Deoksu.
In 2015, Lee played the protagonist in Collective Invention, whose condition is caused by side effects from a newly introduced drug. Collective Invention was screened in the Vanguard section of the 2015 Toronto International Film Festival, marking Lee's first red carpet appearance at an international film festival. He also starred in the two-episode drama Puck!, where he played a loan shark who joins a college ice hockey club. The one-act play was aired on 1 January 2016. The same year, he was appointed ambassador of the “2015 Korea Brand & Entertainment Expo” and received commendation from the trade minister for boosting the Korean Wave industry.
In 2016, Lee starred in tvN's Entourage, a South Korean remake of the American series. He was then cast in the KBS sitcom The Sound of Your Heart, based on the webtoon The Sound of Heart. The web drama was a success in both South Korea and China, gaining 100 million on Sohu TV and ranks No. 1 among Korean dramas on the site.
In 2017, Lee is confirmed to portray a new character in the action comedy The Accidental Detective 2, a sequel to 2015's hit The Accidental Detective. The film will be released in 2018. He will also reunite with It's Okay, That's Love writer Noh Hee-kyung in upcoming drama Live.