In 2021, Reis made her acting debut as the star of the American thriller film Catch the Fair One.

For her performance as a boxer endeavoring to rescue her missing sister, she was nominated for the Independent Spirit Award for Best Female Lead.

Reis was cast in Jean-Stéphane Sauvaire's 2023 film Asphalt City (originally titled Black Flies, adapted from the 2008 novel of the same name by Shannon Burke), starring Sean Penn, Tye Sheridan, and Katherine Waterston.

[25][26] In June 2022, Reis was announced as the co-lead of True Detective: Night Country, the fourth season of HBO's anthology crime series.

Reis starred alongside Jodie Foster as a detective investigating the disappearance of eight men from an Alaskan research station and that event's possible connection to the earlier murder of a young woman, an Iñupiaq activist.

[25][27][16] For her role in Catch the Fair One, Reis won the Jury Award for Best Actress at the 2021 Newport Beach Film Festival.

[29] In 2024, Reis became the first Native American woman nominated for a Primetime Emmy for acting; Reis was nominated for a Primetime Emmy Award for Outstanding Supporting Actress in a Limited or Anthology Series or Movie for her work in True Detective.

[33] That same year, she also received the "Misty Upham Award" at the Red National International Film Festival and was honored with a key to the City of East Providence.

[34][35] On March 28, 2024, a panel of Rhode Island House of Representatives recognized Reis with the Community Hero Award for her advocacy and support of Murdered and Missing Indigenous Women and Girls.