Tig Notaro, an LA-based radio host, returns to her hometown of Bay St. Lucille, Mississippi, to be at the bedside of her ailing mother, Caroline. Suffering from her own recent health problems, Tig attempts to reconnect with her brother, Remy, and stepfather, Bill, both of whom lack the emotional tools to deal with family trauma.

Struggling to accept her mother's death, Tig can't let go of Caroline's possessions.  Unable to leave home, Tig tries to maintain control of her radio show from Mississippi. Seeing that Tig is unable to accept the fragility of life, most pressingly her own, Bill pushes Tig to investigate a disturbing, yet oddly hilarious medical procedure. 

Bill's cat escapes, and Bill blames Tig for letting her out. Tig's biological father, Mick, leads a search party. Assigned to survey the neighborhood, Tig unearths a secret from Caroline's past while Remy encounters a romantic prospect who may be out of his league. Having found a local station where she can record her show remotely, Tig connects with Kate,  the off-beat radio station manager.

Finally feeling physically well, Tig readies for her return to Los Angeles. But before she goes, she is roped into replacing her mother as Mardi Gras Queen at the Bay St. Lucille parade. Remy and Bill are stymied in their search for romance and cats, respectively. Tig searches for Kate at the parade, but instead encounters Jessie, a news reporter who makes her want to stay in town a bit longer.

Tig and Jessie explore the limits of living in the moment. Attempting to connect, Bill attempts to organize a family dinner with Tig and Remy. Remy clumsily pursues a female member of his Civil War reenactment club. Tig and Bill finally have it out over painful events of the past.

Tig returns to Los Angeles and discovers that life has moved on without her. Encounters with friends, an ex-girlfriend, and coworkers all lead her to a crossroads, where a life-altering decision must be made.

Comedian Tig Notaro writes and stars in this semi-autobiographical dark comedy. One Mississippi follows Tig as she returns to her childhood home to deal with the unexpected death of her beloved mother. Struggling with her own health and relationship challenges, she decides to reconnect with her roots to heal and move forward.