- Frances McDormand as Mildred Hayes
- Woody Harrelson as Bill Willoughby
- Sam Rockwell as Jason Dixon
- Abbie Cornish as Anne Willoughby
- Lucas Hedges as Robbie Hayes
- Željko Ivanek as Cedric Connolly
- Caleb Landry Jones as Red Welby
- Clarke Peters as Abercrombie
- Samara Weaving as Penelope
- John Hawkes as Charlie Hayes
- Peter Dinklage as James
- Kerry Condon as Pamela
- Darrell Britt-Gibson as Jerome
- Kathryn Newton as Angela Hayes
- Brendan Sexton III as Crop-Haired Guy
Additionally, Amanda Warren portrays Mildred's friend Denise. Malaya Drew plays Gabriella, a local reporter, and Christopher Berry plays bar patron Tony. Jerry Winsett appears as Geoffrey, the dentist who has his thumb drilled by Mildred. Momma Dixon, Jason Dixon's mother, is portrayed by Sandy Martin. Nick Searcy makes an uncredited appearance as Father Montgomery.
