Born in Richland Center, Wisconsin, Barry moved as a child to Washington. She is one quarter-Filipina, half Irish (each parent is half Irish), and one quarter Norwegian.

She went to the same high school as artist Charles Burns. At The Evergreen State College in Olympia, Washington she met fellow cartoonist Matt Groening, who first published "Ernie Pook's Comeek" in the school paper without her knowledge.

After graduating Evergreen she moved to Seattle, and when she was 23 the Chicago Reader picked up her comic strip, enabling her to make a living from her comics alone. She later moved to Chicago, Illinois. While Barry's work is humorous, the undertones are usually serious. It depicts life as harsh but occasionally joyful. Her work addresses themes of intolerance and psychic pain, and at times includes some starkly left-wing political commentary.[citation needed]

Barry's comics do not strive to depict beauty or demonstrate artistic virtuosity and in that sense are similar to her peers Matt Groening (like her, a graduate of The Evergreen State College), Lloyd Dangle, and Mark Alan Stamaty – but for all their grubbiness are extremely expressive and evocative.

The visual aspect of her work follows the verbal. She has an extreme facility in reproducing the voices of children and adolescents. While some comics purists[who?] complain that her young characters lack elbows, the psychological depth and humanity of those characters calls the reader to take a second look at Barry's drawings. While unconventionally rendered, they carry an undeniable psychic charge legible in the context of her writing.

Barry's early work was rendered with pen and had a distinctly New Wave, '80s look, but she told The Comics Journal that she was forced to give up the pen because it was hurting her wrist, turning to a brush which gave her work a much looser, child-like quality[citation needed].

In her latest books, One! Hundred! Demons! and What It Is, she works with color and collage. These works possess a vitality and visual beauty few would deny[citation needed]. Opening with tens of pages that combine collage with the thesis of the book, What It Is expands the genre of the graphic novel, bringing its bounds closer on one side to collage and on another to the picture book.

Barry has moved her line of comics primarily onto the web.

Barry's books include The Good Times are Killing Me, also a musical play that appeared off-Broadway, The Greatest of Marlys, The Freddie Stories, Cruddy: An Illustrated Novel, One! Hundred! Demons!, a collection of the series published in venues such as Salon.com and, most recently, What It Is.

Her backlist includes Everything in the World, The Fun House, It's So Magic, Naked Ladies Naked Ladies Naked Ladies, Shake a Tail Feather, Down the Street, Big Ideas, Come Over Come Over, Girls and Boys and My Perfect Life.