Joo Jin Mo began his acting career in TV dramas and some minor roles in film. He was first cast as a lead in Dance Dance (1999), for which he underwent extensive dance training. Although the film itself did not perform well, it gave Joo some publicity before he broke through with the box-office and critical hit Happy End. His role as a spurned lover in this psycho-drama attracted considerable notice in Korea, and the film itself also traveled to Hong Kong.

After taking the lead in Kim Ki-duk's mildly experimental Real Fiction (which was shot in 3½ hours without any retakes), Joo took a major role in the much-hyped Musa, set in 14th century China and starring Zhang Ziyi from Crouching Tiger, Hidden Dragon. He also acted in Wanee and Junah, a melodrama about a screenwriter and an animator opposite popular actress Kim Hee-sun.

In 2003 he was rumored to take the lead role in an action blockbuster from Sidus Pictures, and also in the latest film by veteran director Park Kwang-su, but both films were then cancelled due to a lack of financing. Joo's return to the screen came in spring 2004, in the comedy Liar based on the play Run for Your Wife by Ray Cooney. In 2006, he starred in 200 Pounds Beauty.

He was also one of the actors who appeared in the photoshoot "Kolon Christmas Photo Shoot" in 2008, along with co-actors Ko Soo, Song Il-gook, Jang Geun-suk, and Park Jae-jung.

In 2009 he starred in A Frozen Flower with Jo In-sung, a role which won him the 'Best Actor Award' at the 45th Baeksang Art Awards.

In July, 2009, Joo came back to small screen with his newest drama Dream (SBS).