Han Ye-seul won SBS’ Supermodel Contest in 2001, which launched her into the modeling world. In 2003, she made her acting debut in the popular MBC sitcom Nonstop 4, in which she earned a Top Excellence Award at the 2004 MBC Entertainment Awards. Her acting breakthrough came in the 2006 MBC romantic comedy Fantasy Couple, where she played the role of a rude heiress who becomes amnesiac following a yacht accident. She won an Excellence Award at the 2006 MBC Drama Awards as well as the Most Popular Actress for TV at the 43rd Baeksang Arts Awards for her work in the series. In 2007, she starred in the romantic comedy film Miss Gold Digger. The movie’s lackluster box-office performance did not hinder Han Ye-seul from winning multiple Best New Actress accolades from local award-giving bodies. In 2009, she was nominated as Best Actress for TV at the 45th Baeksang Arts Awards for the SBS series Tazza.

In August 2011, Han Ye-seul did not show up for her scheduled filming of the KBS2 drama Myung-wol the Spy and instead flew to Los Angeles. Her then-agency SidusHQ cited conflicts with the drama’s director over her hectic working conditions as the reason for her action. Han Ye-seul eventually returned to South Korea and finished filming for the series. She received intense public backlash over the incident, forcing her to go on a three-year acting hiatus. In 2014, Han Ye-seul made a successful comeback in the SBS romantic comedy Birth of a Beauty. She won an Excellence Award at the 2014 SBS Drama Awards for the series.

Han Ye-seul dated YG Entertainment record producer Teddy Park from 2013 to 2016. On May 13, 2021, she revealed on Instagram that she is dating theatrical actor Ryu Seung-jae, who is 10 years her junior.