The series centers on the Duncan family, who are still adjusting to the birth of their fourth child, Charlotte "Charlie" Duncan (Mia Talerico). When parents Amy (Leigh-Allyn Baker), a nurse, and Bob (Eric Allan Kramer), an exterminator, return to work, they ask their three older children—PJ (Jason Dolley), Teddy (Bridgit Mendler), and Gabe (Bradley Steven Perry)— for help raising their little sister. At the same time, Teddy, PJ, and Gabe try to deal with school and typical social challenges in their life.
The events of each episode become material for a video diary Teddy is making for her younger sister. Teddy hopes the videos will provide useful advice for Charlie after they have both grown up and Teddy has moved out. Also at the end of each video, she (and/or other cast members) states, "Good luck, Charlie" or may even say it indirectly such as "Wish them good luck, Charlie". During the movie, Amy reveals to Teddy that she is pregnant with a fifth child, which Teddy is trying to adjust to but this story plot will not be carried into the actual series until the third season.