Her songs were featured on many series and films including 90210, Hung, Barking Water, The Dark Divide, Resident Alien, Reservation Dogs, Echo, and Unreserved: The Work of Louie Gong.

In 2022, she composed the musical score for the film Fancy Dance starring Lily Gladstone and directed by Erica Tremblay.

Crain taught herself to play guitar and wrote songs based on her short stories the summer before her senior year at Dale High School.

She then founded Samantha Crain and the Midnight Shivers with Jacob Edwards and Andrew Tanz and toured with this band until 2009.

Crain has lent her voice to recordings for Murder By Death, Parker Millsap, Wild Pink, Hamish Hawk, and others.

She has toured with the Avett Brothers, Cotton Jones, Langhorne Slim, Neutral Milk Hotel, The Mountain Goats, Murder By Death,[3] Brandi Carlile, Watchhouse, Buffy Sainte-Marie, Amigo the Devil, John Moreland, The Staves, William Elliott Whitmore, Lucy Rose, Josh Ritter, Adrian Edmondson and the Bad Shepherds, First Aid Kit, Ha Ha Tonka, Deer Tick, Smoke Fairies, Thao and the Get Down Stay Down, Sister Suvi, Ingrid Michaelson, Meiko, Racheal Yamagata, Jenny Owen Youngs, Jessica Lea Mayfield, Emma Gatrill, American Aquarium, Erland and the Carnival, Parker Millsap, Broncho, Ali Harter, Beth Bombara, Berry, Ben Weaver, the Everybodyfields, Bombadil, Gregory Alan Isakov, Ninja Gun, and others.

Rolling Stone magazine reviewed it with 3.5 stars out of 5, saying "Her voice is gorgeously odd — all fulsome, shape-shifting vowels that do indeed billow like fog."

Its two tracks ("It's Simple" and "Cadwell Jungle") were produced by John Vanderslice in San Francisco at Tiny Telephone Studios and features Anne Lillis on percussion.

Produced by John Vanderslice in San Francisco at Tiny Telephone, Crain's third album Kid Face was released on February 19, 2013.

Crain returned to Tiny Telephone to record her 4th full-length album "Under Branch & Thorn & Tree" again with John Vanderslice producing.

It was released July 17, 2015 on 200 gram audiophile quality vinyl boasting its fully analog recording, mixing, and mastering process.

John Calvin Abney, Jesse Aycock (Hard Working Americans, Secret Sisters), Reed Mathis (Tea Leaf Green, Jacob Fred Jazz Odyssey), Anne Lillis (Jessica Lea Mayfield, White Pines), and Meric Long (The Dodos) are all featured musicians on the record.

Rob Shelton, Jason Slota (Thao with the Get Down Stay Down, The Mountain Goats), David Phillips (Tom Waits, Frank Black, John Wesley Harding), Geneva Harrison (Bells Atlas), and Ben Goldberg (The Klezmorium, Bill Frisell, Nels Cline) are all featured musicians on this album.

A music video for the song "Oh Dear Louis" was created by Crain and Jared Evans (Blackwatch Studios).