The strip also features her eight-year-old brother Joe, their parents Frank and Ellen, and their grandparents Nick and Rose, who live next door.

The strip takes place on Buena Vista Avenue in an unspecified city based on Baltimore, Maryland, where the creator grew up.

At school Ruthie dodges the affections of occasionally seen classmate Buggy Crispino (who thinks of himself as a ladies' man and has even complimented Ruthie's mom on her appearance), argues with her snotty rich friend Cylene, and plays with Joe and their ditzy friend James, a poor (and usually dirty) kid who lives down the street.

Grandma Rose has a tendency to meddle in other people's business and gossip, while Nick and Frank tell tall tales to entertain the children.

Originally the creator included two sets of grandparents, but reduced it to only one (Frank's side), with the other—and more eccentric—grandmother, Myrna, making guest appearances.

Ruthie was created as a dark-haired little girl to balance the blond-haired little boys that were already popular in the comic pages.