She then appeared in a 90-minute web film directed by her older brother, commercial Director Bae Doo-han. Titled Red Carpet Dream, it is a biopic of how Bae dreamed of becoming an Actress when she was young, and her 20-year acting career. Commissioned for the 20th anniversary of the Busan International Film Festival and sponsored by MAC Cosmetics, the film screened at the festival as well as on Facebook and cable channel CGV.

A Hanyang University student in 1998, Bae was scouted by a model talent agency while walking in Seoul. This led to modeling clothing for COOLDOG's catalog, amongst others. In 1999 she made the switch to acting before completing her studies at Hanyang University, debuting in the TV drama School. Later that year, she appeared as the ghost in The Ring Virus, a Korean remake of the Japanese horror film Ring.

In 2000, Director Bong Joon-ho cast her in the film Barking Dogs Never Bite for her willingness to do the part without makeup, something other South Korean actresses were unwilling to do. In Kim So-young's documentary Women's History Trilogy (2000–2004), Bae stated her admiration for veteran South Korean Actress Yoon Jeong-hee; Yoon returned the compliment, saying "Bae Doo-na owns her world." In this same documentary, Bae shared how her own most memorable scene was being chased by the homeless man throughout the apartment in Barking Dogs Never Bite. That same year she gave a risque performance (albeit with a body double for the more intense scenes) in Plum Blossom, and slowly started getting more work on television.

This was followed by two more critical successes, 2001's Take Care of My Cat, directed by Jeong Jae-eun, and 2002's Sympathy for Mr. Vengeance, directed by Park Chan-wook.

2003 was less kind to Bae, as she saw both Tube and Spring Bears Love flop at the box office. After completing principal photography on Spring Bears Love, Bae decided to take time off from film, saying: "I never lived even once without having anything to do. The moment a film was presented to the press, I was almost always already shooting the next one [...] I thought by myself: now my first cycle is really over. While I rest a little, I wanted to make a fresh new start."

During her hiatus from the big screen, Bae took up photography, much of which can be seen between her official blog and her published photo-essay books. She also continued to work on TV, starring in Country Princess and Rosemary. Bae finally stepped onto a theater stage in 2004, for a production of Sunday Seoul (not to be confused with the South Korean movie of the same title), a play co-written by Park Chan-wook.

In 2005 Bae gave a memorable turn as an exchange student who joins a band in the Japanese film Linda Linda Linda, then played a divorced woman in the experimental omnibus TV series Beating Heart.

She reunited with Bong Joon-ho in 2006's The Host, which became the highest-grossing film in South Korean box office history. For her role, she trained in archery for months that she was told if she really wanted, she had enough talent to make it at an amateur level. She then returned to television, through the series Someday and How to Meet a Perfect Neighbor.

After winning accolades for Air Doll, a 2009 film by Japanese Director Hirokazu Koreeda about an inflatable sex doll that develops a soul and falls in love, Bae made back-to-back TV series in 2010, playing a high school Teacher in Master of Study, and a night club singer in weekend drama Gloria.

Bae made her English-language, Hollywood debut in Cloud Atlas, as Sonmi~451, a clone in dystopian Korea. She also played the minor roles of Tilda Ewing, the wife of an abolitionist in pre-Civil War America, and a Mexican woman who crosses paths with an Assassin. Co-directed by The Wachowskis and Tom Tykwer, the US$100 million adaptation of David Mitchell's novel premiered at the 2012 Toronto International Film Festival to divisive reviews, though Bae's performance was unanimously praised by critics.

Back in Korea, Bae next starred in the 2014 film A Girl at My Door, directed by July Jung and produced by Lee Chang-dong. Playing a small-town police officer who tries to save a mysterious young girl she suspects is a victim of domestic violence, Bae said she was so fascinated by the story and emotionally challenging role that she decided to star in the movie without pay three hours after reading the script. The film premiered in the Un Certain Regard section of the 2014 Cannes Film Festival, and Bae later won Best Actress at the Asian Film Awards.

In 2015, she reteamed with the Wachowskis for their space opera Jupiter Ascending, in which she played a small supporting role as a bounty hunter. This was followed by Sense8, an American science fiction series created by the Wachowskis (in Bae's third collaboration with them) and co-written by J. Michael Straczynski. About eight strangers from different cultures and parts of the world who share a violent psychic vision and suddenly find themselves telepathically connected, Sense8 began streaming on Netflix in 2015.

Bae returned to Korean TV screens in 2017 with mystery legal thriller Stranger, playing a passionate police officer. The series was a hit and gained favorable reviews for its tight plot, gripping sequences and strong performances. Bae is set to appear next in omnibus romance film The Romantic and police corruption thriller Drug King. She was also cast in Netflix's upcoming zombie series Kingdom.

Back on the big screen, Bae starred alongside Ha Jung-woo in the survival drama film The Tunnel. She then teamed up with Japanese Director Shunji Iwai and actor Kim Joo-hyuk for the short film, Chang-ok’s Letter.