Son Ye-jin first appeared in a supporting role in Park Ki-hyung's film Secret Tears in 2000, and then went on to take the leading role in television dramas such as Delicious Proposal, Sun-hee and Jin-hee, and Great Ambition. Her first high-profile role in cinema was in Im Kwon-taek's Chi-hwa-seon, which screened at Cannes and took home a Best Director award in 2002.
Son then cast off her nice girl image in her next projects. She took on the roles of a con Artist in The Art of Seduction, an ambitious reporter in Spotlight, a femme fatale in Open City, and a divorcée in the critically acclaimed series Alone in Love. In 2008, her portrayal of a polyandrous woman in My Wife Got Married bagged her Best Actress honors from the prestigious Blue Dragon Film Awards and other local award-giving bodies.
In 2012, Son starred in her first blockbuster The Tower, a remake of the 1974 Hollywood disaster film The Towering Inferno. She returned to television in 2013 in the revenge drama Shark (also known as Don't Look Back: The Legend of Orpheus), then headlined Blood and Ties, a thriller about a daughter who suspects that her Father was involved in a kidnap-murder case.
Son reunited with Shark costar Kim Nam-gil in the 2014 period adventure film The Pirates, which received mixed reviews but was a commercial hit and won Son the Best Actress award at the Grand Bell Awards. Son next starred in the black comedy Bad Guys Always Die opposite Taiwanese actor Chen Bolin, a Chinese-Korean co-production that was filmed on Jeju Island.
In 2016, Son reunited with My Wife Got Married co-star Kim Joo-hyuk in The Truth Beneath, a political thriller. She won Best Actress at the 25th Buil Film Awards and 17th Busan Film Critics Awards for her performance. She then played Princess Deokhye in the biopic The Last Princess, helmed by April Snow Director Hur Jin-ho. The film drew positive reviews by critics and went on to become a box office hit, grossing US$40.35 million worldwide. Son was praised by critics for her "outstanding" performance in her portrayal of "the unfathomable depths of the emotional ups and downs of Deokhye".
In 2017, Son was cast in the crime thriller Negotiation alongside Hyun Bin.
In 2018, Son starred alongside So Ji-sub in the romance film Be with You, based on the Japanese novel of the same name. The same year, Son returned to the small screen after five years with JTBC's romance drama Something in the Rain.