One year later after the Flight 180 curse from the first film, Kimberly Corman (A. J. Cook) has a precognition of a pile-up in Route 23, killing everyone involved. She stalls her car on the entrance ramp to the highway with her friends Shaina (Sarah Carter), Dano (Alex Rae), and Frankie (Shaun Sipos) inside so that motorists who would've otherwise died are spared. This stops teacher Eugene Dix (T.C. Carson), mother Nora Carpenter (Lynda Boyd), her son Tim (James Kirk), pregnant Isabella Hudson (Justina Machado), lottery winner Evan Lewis (David Paetkau), drug addict Rory Peters (Jonathan Cherry), selfish Kat Jennings (Keegan Connor Tracy), and Officer Tom Burke (Michael Landes) from going further to the highway. (In Kimberly's premonition, a log splattered Tom's head, Eugene was crushed by his motorcycle. Rory's car was hit by a truck, blowing it up, Kat hit a log and violently flipped over, Nora & Tim blew up in their car, and Evan was burned alive, and put out of his misery by a truck. Notice that this is the order everyone died in, but backwards). Kimberly’s premonition turns into a horrific reality while Tom questions her. An 18-wheeler truck passes by, almost hitting Kimberly, but kills Shaina, Dano, and Frankie.
At a police station, Tom asks Kimberly how she could know that a pile-up was going to happen. They all conclude that Kimberly experienced the same feeling Alex Browning did. The other survivors realize they’re just wasting their time and they all flee. Later, Evan is impaled by a fire escape ladder through his eye after escaping a microwave-induced fire in his apartment. Tom believes that Kimberly needs help from the last survivor of Flight 180, Clear Rivers (Ali Larter). When Alex was struck in the head by a falling brick, Clear has checked herself into a mental asylum.
Kimberly visits Clear Rivers in the mental institution, where Clear tells Kimberly to be careful, because the order has reversed itself. Kimberly then becomes frustrated after Clear only suggests to her to keep herself safe inside the asylum, and let her friends die. Later, Clear decides to help them after all.
Meanwhile, Tim almost dies of choking at a dentist's office when a plastic fish gets caught in his mouth after breathing in too much laughing gas, but is saved by a nurse. As Tim and Nora go outside, Tim chases a flock of pigeons, causing a crane to drop a giant glass window on Tim, crushing him. Clear then takes Kimberly and Tom to William Bludworth (Tony Todd), who only tells them that “new life defeats death”. Tom realizes new life could mean pregnancy, and orders some officers to look for Isabella. As the survivors and Clear gather inside Tom’s apartment, Eugene accidentally triggers a mousetrap, which knocks a boat that almost kills Clear. Meanwhile, the cops find Isabella. Nora and Eugene leave by taking the elevator, and Nora is decapitated by the malfunctioning elevator doors after getting her hair caught in the hooks of a set of prosthetic limbs that an old man was carrying. Scared, Eugene takes Tom's gun and shoots himself in the head six times, but fails to kill himself, even though the gun is fully loaded.
At the prison, Isabella’s water breaks. As she and the cop leave using Isabella’s white van, the survivors talk about themselves cheating death inside Kat’s Ford Expedition. There, it is revealed that they all wouldn’t be alive if the Flight 180 survivors were still alive, which is why the order has reversed itself: Kimberly should have died in a thug fight that killed her mother, but was lured away by the news about Tod Waggner’s strangulation in his shower. Tom should have died in a shootout which killed his partner, but was busy cleaning the remains of Billy Hitchcock. Eugene should have died in his classroom after a student brought a knife to school, but instead was in Mt. Abraham High to replace the deceased Ms. Valerie Lewton. Rory should have died in an ill-fated theater, but ceased going there after seeing Carter Horton being hit by a falling marquee. Kat should have died in a bed-and-breakfast hotel where a gas leak suffocated all customers, but was delayed due to the bus she was on killed Terry Chaney.
They don’t notice that they are heading toward a log, popping a tire, causing a PVC pipe to fall through Kat’s Expedition and puncture Kat's headrest. The Gibbons and their son Brian (Noel Fisher) witness this, and Brian helps Kat, who is almost impaled by the pipe. Eugene is then rushed to the hospital while the trio stays in the field. A news van arrives, almost hitting Brian, who is warned by Rory. A fireman uses the Jaws of Life to pry the log out of the car, but sets off the airbag accidentally which impales Kat's head onto the sharp pipe. Kat’s cigarette falls, igniting a trail of gasoline heading towards the news vans gas tank. The news van explodes, sending a barbed-wire fence toward Rory, slicing him into 3 pieces. Clear, Kimberly, and Tom go to the hospital to find Isabella & Eugene. Meanwhile, Kimberly has a vision of Dr. Kalarjian trying to choke someone. As they arrive, she and Tom find Isabella and her baby safe with Dr. Kalarjian. They continue rejoicing, just as Kimberly finds out Isabella wasn't even supposed to die at the pile-up. Meanwhile, Clear finds Eugene’s oxygenated room. As she opens the door, it disconnects an electrical plug, setting off a spark that causes the room to be incinerated, killing Clear and Eugene. As Kimberly and Tom realize that Clear and Eugene are dead, Kimberly understands that she must sacrifice herself by driving the van into the lake. As she does this, Tom saves her. She then wakes up, seeing Dr. Kalarjian reviving her with Tom welcoming her back.
Weeks later, Tom and Kimberly celebrate at the Gibbon’s farm. Brian then goes back to the grill for more barbecues. The Gibbons then tell Kimberly and Tom about Brian almost being hit by the news van earlier, but was saved by Rory. As the two realize it’s not over yet, the grill explodes and kills Brian. Brian's severed arm lands on his mother's plate, much to her horror.
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