A.N.T. Farm revolves around Chyna Parks (China Anne McClain), a 11-year-old musical prodigy, who has just become the newest A.N.T. (Advanced Natural Talents) in the A.N.T. program at Webster High School in San Francisco, California. On her first day, she meets Olive Doyle (Sierra McCormick), an odd girl who has an eidetic memory, and Fletcher Quimby (Jake Short), an artistic genius (but otherwise quite dim) who falls deeply in love with her when they first meet. They soon become her best friends at the high school. They proceed to go on multiple adventures, using their talents to their advantage.
The school's "it" girl, Lexi Reed (Stefanie Scott), proceeds to bully Chyna, thinking of her as competition in being the star of the school. Chyna's bumbling older brother, Cameron (Carlon Jeffery), attempts to avoid Chyna in high school as much as he can, afraid she will be an embarrassment to him. Lexi's best friend Paisley, (Allie DeBerry) and Chyna, Olive, and Fletcher's friend Angus (Aedin Mincks) share a major-recurring role on the series.
Season 3 now takes place at a boarding school instead of at Webster High School.