It follows the adventures of assorted anthropomorphic animals, centering on Ozy and Millie, two young foxes attending North Harbordale Elementary School in Seattle, Washington, contending with everyday elementary school issues such as tests and bullies, as well as more surreal situations.

[3] The strip mostly concentrates on character interaction, but sometimes veers into commentary based on author Simpson's own political views.

Ozy and Millie originally started as a printed comic strip in a Washington college newspaper, the Copper Point Journal, in 1997, with Simpson using ink and brush as drawing implements.

He is adept at letting Millie's pranks pass by without effect, but he does suffer bullying at the hands of the school jock, Jeremy, who likes to stuff Ozy into trash cans.

[17][18] Millicent Mehitabel Mudd, better known as Millie, is a ten-year-old red fox girl who is best friends with Ozy.

Unlike Ozy, who is calm, Millie is chaotic and crafty, both in the destruction she leaves behind and the ways she devises of avoiding work (or attempting to).

[15][16][18] She is a rebel and is opposed to any form of authority, which regularly leads to confrontations with both her teacher, Ms. Sorkowitz, and her mother, Mililani Mudd.

However, her rebellions are mostly limited to annoying her mother, playing jokes on Ozy and disrupting the peace at school; none of which matters any less to her, as long as she has fun doing it.

[18] Avery's curious younger brother, Timulty, constantly undermines his coolness, although he simply likes being with him and his friends.

The two major antagonists are Felicia the sheep, a "popular girl" who teases Millie for being too individualistic,[18] and Jeremy the jock rabbit who bullies Ozy for few reasons.

Ozy's dragon cousin, Isolde, is known for her unusual methods in her job in journalism, and, like Llewellyn, is in charge of various conspiracies.

"[19] In 2006, Patten still claimed that, "Ozy and Millie is one of the top anthropomorphic cartoon strips on the Internet," although he did also comment negatively about the loss of colour in between changes of printed editions of books.