In 1998, an eight-year-old Shin Se-kyung was featured on the poster and cover of Seo Taiji’s solo album Take Five. She also starred in the popular children show Ppo Ppo Ppo. In 2009, she played the teenage Princess Cheonmyung in the top-rating MBC sageuk Queen Seon-deok. This was followed by her breakthrough role in the hit MBC sitcom High Kick Through the Roof, which won her Best New Actress at the MBC Entertainment Awards.  In 2011, she acted alongside veteran actor Song Kang-ho in the action drama film Hindsight, which earned her Best New Actress nominations at the Blue Dragon Film Awards and the Grand Bell Awards. That same year, she took home an Excellence Award at the SBS Drama Awards for her performance in the series Tree with Deep Roots. In 2013, she was paired with Song Seung-heon in the MBC melodrama When a Man Loves, in which she bagged an Excellence Award at the MBC Drama Awards. In 2015, she landed a main role in the SBS sageuk Six Flying Dragons, which gave her an Excellence Award at the SBS Drama Awards. In 2019, she received a Top Excellence Award at the MBC Drama Awards for her portrayal of a free-spirited female historian in the sageuk Rookie Historian Gu Hae-ryung.

In October 2010, it was revealed that Shin Se-kyung was dating Jonghyun of the South Korean boy group SHINee. In June 2011, their agencies confirmed the couple’s breakup. Shin Se-kyung took up a Performing Arts degree at the Chung-Ang University. She can speak English fluently. In 2017, she revealed in an interview for her drama Bride of the Water God that she has a severe water phobia.