Chuck Bartowski (Zachary Levi) is a socially awkward twenty-something in Burbank, CA who works as a computer expert at the Nerd Herd at his local Buy More (a parody of Best Buy's Geek Squad), a local electronics retailer (a CompUSA store was used), with his best friend, Morgan Grimes (Joshua Gomez). Chuck's sister Ellie (Sarah Lancaster) is a doctor who is constantly looking out for his best interests and wants to help him find a girlfriend. Also joining the cast is Ellie's fiance, Devon "Captain Awesome" Woodcomb (Ryan McPartlin), also a doctor looking out for Chuck's social life. On the night of his birthday party, Chuck receives an e-mail from his former Stanford University roommate, Bryce Larkin (Matthew Bomer), who is now a "rogue" CIA agent. When he opens it, the entire database of all the US government's secret information — a neural supercomputer called the Intersect — is subliminally embedded into his brain. Both the National Security Agency and the Central Intelligence Agency want the intelligence returned to them and dispatch agents of their own — Major John Casey (Adam Baldwin) and Sarah Walker (Yvonne Strahovski) — to retrieve the data.
Since the disk with the government information was stolen by Bryce and destroyed in his attempted escape, and since Chuck experiences "flashes" of information from the database activated by certain triggers around him (such as faces, guns, watches, and other objects), he must use the knowledge he now possesses to help the government thwart assassins and international terrorists — upending his previously uneventful life. In order to preserve their safety, Chuck must keep his new-found occupation a secret from his family and friends, forcing Casey and Walker to establish an uneasy alliance and secret identities; Walker poses as Chuck's girlfriend and takes a cover job at the local restaurant next to the Buy More (formerly Wienerlicious, currently Orange Orange) while Casey gets a job at the Buy More, with the shared goal of protecting Chuck at all costs.