The series stars WordGirl, an alien with superpowers whose secret identity is Becky Botsford, a 10½ year old fifth grade student. WordGirl was born on the fictional planet Lexicon (also a term referring to the vocabulary of a language or to a dictionary) but was sent away after sneaking onto a spaceship and sleeping there. Captain Huggy Face, a monkey who was a pilot in the Lexicon Air Force, piloted the ship, but lost control when WordGirl awoke, and crash-landed on Earth (more specifically in Fair City), a planet that affords WordGirl her superpowers, including flight and super strength. WordGirl utilizes these powers to save her adoptive home, using her downed spacecraft as a secret base of operations. WordGirl and Captain Huggy Face fight crime together.

WordGirl was adopted and provided an alter ego by Tim and Sally Botsford, who gave her the name Becky. While in her alter ego, she has a younger brother, TJ, obsessed with WordGirl, but still unknowingly a typical sibling rival to Becky. The Botsford family keeps Captain Huggy Face as a pet, naming him Bob. Becky attends Woodview Elementary School, where she is close friends with Violet Heaslip and has a crush on school newspaper reporter Todd “Scoops” Ming.

WordGirl tries to balance her superhero activities with her "normal" life. Doing battle with a rather odd grouping of villains, such as the Butcher, who can call into existence most any type of meat; senior citizen Granny May, with her knitting needles and projectile yarn; her former friend Professor Steven Boxleitner, who became the evil Dr. Two Brains thanks to an albino mouse fusing his brain with the animal; ten-year-old genius and colossal robot builder Tobey McCalister; and The Whammer, who speaks by interjecting the word "wham" in the most inopportune sentences. At the same time, she must worry about maintaining her second life as Becky, keeping people from discovering the truth and living normal family situations.