One year after the first film, college student Kimberly Corman is heading to Daytona Beach, Florida for spring break with her friends, Shaina McKlank, Dano Estevez, and Frankie Whitman. En route, Kimberly has a premonition of logs falling off a semi, causing a massive car crash that kills everyone involved. She stalls her car on the entrance ramp, preventing several people from entering the highway, including Lottery winner Evan Lewis; widow Nora Carpenter and her fifteen-year-old son Tim; businesswoman Kat Jennings; stoner Rory Peters; pregnant Isabella Hudson; high school teacher Eugene Dix; and Deputy Marshal Thomas Burke. While Thomas questions Kimberly, the pileup occurs. Shaina, Dano and Frankie are killed by a speeding truck, but Kimberly is saved by Thomas.
The survivors are brought to the police station, where they learn about the curse of Flight 180. Later, a chain reaction causes a fire in Evan’s apartment which he barely escapes; but when Evan slips the escape ladder falls and impales his eye. Thomas researches the survivors of Flight 180, and discovers that Alex Browning was killed by a falling brick. Kimberly visits Clear Rivers, the last survivor of Flight 180, who is now a voluntary inmate at a psychiatric ward. Clear refuses to help, but while arguing with Kimberly realizes that the survivors are dying in reverse, and warns Kimberly to look out for “signs” of Death. Upon arriving home, Kimberly has a vision of a flock of pigeons attacking her and she and Thomas rush to save Nora and Tim, but they arrive too late and Tim is crushed by a glass pane at a dentist. Clear decides to help and introduces Kimberly Thomas to mortician William Bludworth, who tells them that only “new life” can defeat Death. They believe that if Isabella has her baby it will ruin Death’s plan and they will all be safe.
Isabella is accused of driving a stolen van and taken into custody, while the other survivors reunite for safety. After Nora is decapitated by malfunctioning elevator doors, the group leaves to find Isabella, who has gone into labor at the police station, while the policeman on duty rushes Isabella to the hospital in her van. Along the way they discover they have all cheated death twice; had it not been for the survivors of Flight 180 they would all be dead, which explains why the survivors are dying in reverse. Since Thomas saved Kimberly from being hit by the truck, she is last on Death’s list.