She was born in Alexandria, Virginia. Her parents divorced when she was a child, so Case ended up spending most of her time with her grandparents. Her grandmother introduced her to country music.
Case's early life was spent bouncing around the country with her mother and her stepfather, who was an archaeologist. By the time she was 15, she'd lived in Massachusetts, Vermont, Oregon, and Washington. When she reached 15, she struck out on her own and ended up in Tacoma, Washington, which at that time was a very rough and violent city, but one that Case calls her hometown.
Case started drumming with a Tacoma band named Del Logs and the Propanes. She played in a venue called the Community World Theater, which was the first venue in which Nirvana played under the name Nirvana. She also worked at Tacoma landmark Bob's Java Jive.
During this time, fellow Propane musician Laura Woods introduced Case to a lot of music that would shape her personal vision. "Swing Down Sweet Chariot" by Bessie Griffin and Her Gospel Pearls was particularly influential.
After meeting the band Girl Trouble, she spent some time go-go dancing on stage during their performances. Girl Trouble wrote a song for her, named "Neko Loves Rock'N'Roll," which appears on their 1990 album Thrillsphere. This relationship also led to Case meeting CBC radio producer and musician Grant Lawrence, who saw Case dancing at a gig in Vancouver. He'd heard the song "Neko Loves Rock'N'Roll" but only then did he realize it was about a real person. The two struck up a friendship, and Case put together a gig in Tacoma for Lawrence's band, the Smugglers.
Case maintained her relationship with the Smugglers and eventually designed the cover of their 1993 album, In the Hall of Fame. Smugglers' guitarist Dave Carswell and Case fell into a relationship that took them to Vancouver, with musicians closer to Case's age and experience level. Here, she met Bill Baker, who co-owned Mint Records.
When the drummer of Mint Records' band Cub couldn't play for one of the opening shows of a West Coast tour, Case took the young woman's place and completed the tour with the band.
In 1994, Case started classes at the Emily Carr Institute of Art and Design. In 1995, she still found the time to do another tour with Cub. In 1998, Case graduated with a BFA.
She released her first solo album, The Virginian, in 1997. Mint was hesitant about recording an album of country songs when they considered Case to be a "rock and roll girl," but they had faith in her voice and her talent. The album launched a career that is still going strong as of 2018.
Case's backing band is named "The Boyfriends."
Case played with Carolyn Mark in a duo named the Corn Sisters. In talking about the band, Mark explained, "Neko woke up there and said, 'I just had a dream that we were a traveling act called the Corn Sisters and we sang songs about cheating. Let's do it!'"
Playboy declared Case the "Sexiest Babe of Indie Rock" after their April 2004 poll, but she rejected their offer to do a nude spread. "I didn't want to be the girl who posed in Playboy and then - by the way - made some music," she told Entertainment Weekly. "I would be really f--king irritated if after a show somebody came up to me and handed me some naked picture of myself and wanted me to sign it instead of my CD."
She clashed with Playboy again on May 21, 2014, when the magazine tweeted out a story that calling Case a "woman in music." Case tweeted back, "Am I? IM NOT A F--KING 'WOMAN IN MUSIC', IM A F--KING MUSICIAN IN MUSIC!"
In 2009 Case told Exlaim!: "Storytelling is easiest for me. I'm pretty boring, so writing about myself would be no great service to the listener. Yes, I'm in there, and I think the only autobiographical song I've ever written is on this record [Middle Cyclone], but I shy away from love songs. I guess I'm just not interested in them, aside from the great classic ones I love. Every now and again someone will write one that just blows my mind. I'm pretty impulsive in what I write. I get something down and then I'm desperate to build a song around it or to hit the notes. I generally write songs that are too hard to sing."
Peter Robinson's novel Friend of the Devil mentions Neko Case. Detective Banks, the main character, is marked by his impeccable musical tastes. In the middle of the book he listens to Case song "That Teenage Feeling."
Case sang on a song titled "69" used in Adult Swim. She also starred in an Aqua Teen Hunger Force episode called "Sirens," where she played the character Chrysanthemum.