In 2013, Brown made her acting debut as a guest star in the ABC fantasy drama series Once Upon a Time in Wonderland, a spin-off of Once Upon a Time, portraying the role of Young Alice. In 2014, she had a starring role in the BBC America paranormal drama-thriller series Intruders as Madison O'Donnell. She then made guest appearances in the CBS police procedural drama NCIS, the ABC sitcom Modern Family, and the ABC medical drama series Grey's Anatomy.
In 2016, Brown played Eleven in the Netflix science fiction horror series Stranger Things. Her portrayal received critical acclaim and she was nominated for the Screen Actors Guild Award for Outstanding Performance by a Female Actor in a Drama Series and the Primetime Emmy Award for Outstanding Supporting Actress in a Drama Series. She won the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series with her co-stars and won the 43rd Saturn Award for Best Performance by a Younger Actor in a Television Series. For her role as Eleven in the second season of Stranger Things, she got her second Emmy nomination in 2018.
In November 2016, Brown starred in the music video for Sigma and Birdy's single "Find Me". Since November 2016, she has appeared in commercial advertisements for Citigroup. In January 2017, she made her modelling debut in Calvin Klein's By Appointment campaign. The following month, she was signed to the agency IMG Models. She appeared in the campaign of the Italian brand Moncler in the summer of 2018.
Brown will make her feature film debut in the sequel to Godzilla, Godzilla: King of the Monsters. She will reprise her role in Godzilla vs. Kong.
In January 2018, Brown was cast to star and produce the film adaptation of Enola Holmes Mysteries. On 20 April 2018, she became the youngest person ever to be included in TIME magazine's list of the 100 most influential people in the world and on 20 November 2018, it was announced that she had become the youngest person ever to be appointed as a UNICEF Goodwill Ambassador. In November 2018, EA Games announced that Brown collaborated with The Sims 4 programmers to feature in the Sims 4 Positivity Challenge. She was named by Time magazine as one of the most influential teens of 2017 and of 2018. In 2018, The Hollywood Reporter named Brown among Hollywood's top thirty stars under age eighteen.
In March 2019, it was announced Brown will be starring in the film adaptation of The Thing About Jellyfish by Ali Benjamin as Suzy. Also in March 2019, she became the ambassador of UEFA's Together #WePlayStrong campaign.
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