It was founded in 1952 to house the collection of Charles and Emma Frye and has since grown to include rotating temporary exhibitions of emerging and contemporary artists.

[5] After Charles and Emma Frye had both died and following the sale of their home in 1941, many of their collected paintings, overseen by Walser Greathouse, were moved to the meat plant on Airport Way in SoDo, Seattle.

[5] The stored artwork survived a major fire at the plant on Feb. 18, 1943, following the crash of a B-29 bomber prototype, then a top-secret military project.

[4] The Fryes' historic collection consisted of representational art works, with a tendency toward "the dark, the dramatic, and the psychological" rather than "the genteel".

[7] Exhibitions have included "Subspontaneous: Francesca Lohmann and Rob Rhee," featuring sculptures involving natural forces and ecological growth,[8] "Agnieszka Polska: Love Bite,"[9] and "Unsettling Femininity: Selections from the Frye Art Museum Collection.

[14] In 2020, amid the COVID-19 pandemic, the museum temporarily closed for in-person visits and provided online art viewing and educational opportunities through the Frye From Home program.