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In 2016, Keough had her breakthrough role as an escort in the first season of the anthology series The Girlfriend Experience, earning a Golden Globe Award nomination for Best Actress. Her performance as a wayward young woman in the drama American Honey (2016) earned her further acclaim, including an Independent Spirit Award nomination for Best Supporting Female.

Keough went on to star in the horror film It Comes at Night (2017) and in Soderbergh's heist film Logan Lucky (2017); she then appeared in the horror films The House That Jack Built (2018) and The Lodge (2019). Following a leading role in the comedy-drama Zola (2020), Keough starred in the Amazon Prime Video thriller series The Terminal List (2022) and the drama miniseries Daisy Jones & the Six (2023). The latter earned her nominations for another Golden Globe and a Primetime Emmy Award.

Keough is a co-founder of the production company Felix Culpa. She has co-directed the drama War Pony (2022), which won the Caméra d'Or. She became the sole owner of Elvis Presley's estate, Graceland, following her mother, Lisa Marie Presley's death in 2023.