Sean Jones (NATHAN PHILLIPS) is an unassuming surfer and off-road biker who -- while biking through inland Hawaii -- accidentally stumbles upon mobster Eddie Kim (BYRON LAWSON) killing a government prosecutor. A marked man, Sean is nearly killed by some of the crime lord's thugs, but just then FBI agent Neville Flynn (SAMUEL L. JACKSON) swings into action and saves him.
With no other alternative, Sean reluctantly agrees to be flown to California to testify against Kim, but rather than take the government plane as expected, Flynn and fellow FBI agent John Saunders (MARK HOUGHTON) sneak him onto commercial airliner South Pacific Air 121.
Needing the secure space, Flynn orders that everyone be kept out of first class, meaning flight attendant Claire Miller (JULIANNA MARGULIES) has to inform the passengers -- such as the snobby Mercedes (CHEL BLANCHARD) and her pet dog, as well as germ phobic recording artist Three G's (FLEX ALEXANDER) and his small entourage including Troy (KENAN THOMPSON) - that they have to sit back in coach with everyone else, including young brothers Curtis (CASEY DUBOIS) and Tommy (DANIEL HOGARTH) who are traveling by themselves, and single mother Maria (ELSA PATAKY).
But little do they -- or copilot Rick (DAVID KOECHNER) and flight attendants Tiffany (SUNNY MABREY), Ken (BRUCE JAMES) and Grace (LIN SHAYE) -- realize that Kim has managed to smuggle a crate of deadly snakes onto the plane, designed to open when a certain altitude is reached. Enraged by the pheromone-laced leis onboard, the snakes go crazy, quickly killing the pilot and various passengers, while also inadvertently shorting out some of the plane's electronics.
As FBI agent Hank Harris (BOBBY CANNAVALE) tries to round up herpetologist Steven Price (TODD LUISO) and all of the necessary antivenom back in Los Angeles, Flynn and the remaining crew and passengers do what they can to avoid the snakes and try to land the plane.