She is known for her appearances in the Korean historical drama Dae Jang Geum (2003), and as a revenge-seeking single mother in Park Chan-wook's crime thriller film Lady Vengeance (2005).

She would be playing dual roles as Shin Saimdang, a famed Joseon-era artist and calligrapher as well as a modern-day Korean history lecturer.

[25] In 2023, she came back to the small screen with the leading role in Maestra: Strings of Truth, playing Cha Se-Eum, a world-renowned orchestra conductor who keeps a big, dangerous secret.

[34] In 2016, she helped a Vietnamese girl who went to Korea to treat her brain tumor by donating 37 million won for the operation and other medical bills.

[36] Lee also became the first actress to join the "Chime for Change" campaign of Gucci to "raise funds and awareness for projects promoting education, health, and justice for girls and women" around the world.

[40] On May 1, 2022, Lee donated 100 million won to the Sowon Foundation Office in Yangpyeong City Gyeonggi-do Province to assist patients who have difficulty getting out of the house due to childhood cancer or rare diseases.

[43] On January 22, 2023, Lee donated 50 million won to residents affected by the fire in Guryong Village, Gangnam District, Seoul.

[45] In November 2023, Lee donated ₩50 million to aid humanitarian efforts for children hurt in the Israel-Hamas war, the Korean Red Cross announced on 21.

Her urban image with her raised hair and trench coat collar left a strong impression on viewers, and Lee Young-ae, who was studying "German Language and Literature" at Hanyang University at that moment, rose to stardom with the modifier Oxygen Lady.

[50] In January 2017, Lee became the cover face of the February issue of Elle Korea magazine to promote the Spring - Summer 2017 collection of Italian luxury fashion house Valentino.

[51][52] In January 2021, she was the cover face of the February issue of Marie Claire Korea to represent the Spring - Summer 2021 collection of Spanish-French luxury fashion house Balenciaga.

[53] She appeared on the cover of Noblesse Magazine June 2021 Issue to present the Van Cleef & Arpels's "Palmyre", "Treasure of Rubies", "the Snowflake", "Arche de Noé", "Pierres de Caractères" and "Les Ateliers Créations" high jewelry collection and the bag line for French luxury leather goods brand Fauré Le Page.

[54][55] In September 2021, she appeared on the cover of Dazed Korea Fall 2021 Edition Issue to present the Aria Fall/Winter 2021 collection and the Diana bag line for Italian luxury brand Gucci.

[58] In the Arena Homme + Korea April 2024 issue, for which she was the cover star, Lee represented the Bottega Veneta Spring/Summer 2024 ready-to-wear collection.

[60] In July 2024, Lee appeared on the cover of the August issue of Harper's Bazaar Korea to promote the Pre-Fall 2024 Collection by American luxury fashion brand Ralph Lauren.