The film opens with a pregnant woman waiting for a bus at night. Shortly after she boards the bus #657, the thieves hijacks the bus.
One week earlier, casino owners detective Dog (or Derrick) (Morris Chestnut
) and Mr. Pope (Robert De Niro
) interrogates a couple about the whereabouts of money. After man eventually answers to them, Dog fatally shoots them both.
Luke Vaughn (Jeffrey Dean Morgan
), a man working in a casino, visits his sick daughter in a hospital. But, the money he earn from the casino is not enough to pay the medical bills. Vaughn promises to the doctor that he will pay for her operation by Friday or else his daughter will die.
Back to the casino, Vaughn plans to rob the money with the help of his co-worker, Cox (Dave Bautista
). Cox discusses about the every night lifestyle of the casino, especially the money. Later, Vaughn having a meeting with Pope about the money. Vaughn desperately needs at least $300,000 for his daughter's medical bill but Pope refuses and instead he fires him.
Cox, Vaughn, and a man (we don't know what his name was) agreed to rob the money at the casino tonight. After they obtain the money in the casino, things go wrong when one of the employees sees them. One of the thieves shoots the employee dead as he runs away. The thieves manage to run for their lives after they encountered the shootout between Dog and his employees, wounded one of the thieves. The car waiting for them drives away in terror, so the thieves are forced to hijack the bus 657 to escape. Not knowing for the thieves, the police car, dispatched by Officer Kris Bauhaus (Gina Carano
), is stalled few blocks behind from the bus. Kris hears the gunshots coming from the bus and pursuits it. As they board the bus, Vaughn and takes off the masks, making the pursuing Dog and his men identifies them. Cox and the man also took the mask off. As Kris investigates the bus, the thieves and the passengers acts normal. But when Kris wants the bus to pull over, Cox fires his shootgun onto Kris but she dodges. The rest of the police cars pursuit and making roadblocks far away before the bus. To make Kris negotiate with them, Vaughn writes the passenger's phone number in the bus window. Vaughn tells Kris to the captain to clear the roadblocks but he refuses. Vaughn threatens Kris to kill some of the passengers including the boy and the pregnant woman if she doesn't comply. When she does, Kris runs over the roadblocks, allowing the bus to enter the interstate.
The next morning, the bus continues to drive in the interstate. A wounded thief is dying, so Vaughn calls one of the passenger, which is veterinarian student, to take care of him. While Cox is taking a call to Jono - who aids the thieves, a male passenger helds his knife to Vaughn and aims a gun to Cox but Vaughn subdues him and takes his knife away. Cox orders the bus driver to head to Galveston, Texas, unfortunately the fuel is not enough to go that place, so Vaughn calls for fuel tanker.
Kris is driving fuel tanker to refuel the bus while Detective Marconi - who allies Kris when she is about to relieve from duty - monitors them via a police helicopter. While refuelling, Vaughn allows the two hostages (pregnant woman, named Pauline, and the boy) to release. Understanding about Vaughn's motive in order to survive his sick daughter, Kris allies Vaughn. Meanwhile, Dog knows the location of Jono through the police radio scanner.
A wounded thief is losing a lot blood, so Vaughn calls Marconi for medical kits. However, a wounded thief dies when he is being treated by the veterinarian - but she has no idea how the thief dies in unknown reason. After Cox attacks Marconi - for allegedly done with his thief partner - then throws him out of the bus, the SWAT Team throws the smoke grenade and begins to attacking Vaughn and Cox. After they managed to throw the other SWAT members, one of the SWAT member pops out a tire, eventually crashes it near the bridge. Most of the passengers got the minor injuries.
Now the police surrounding the bus, Cox held the bus driver hostage in front of them. Cox lets the passenger to call the news on the line via cell phone in order to hear his threatening voice on live news. The bus driver is presumably shot dead by Cox but it is revealed that Vaughn shot Cox dead, allowing the bus driver to live. Vaughn receives a call from his daughter saying that Kris is already there to help his hospital bills. After that, Vaughn radios Marconi to call the mechanic to fix the tires and threatens to kill any hostage if someone, including police escorts, choppers, follows them. Vaughn release all the hostages and the bus departs once the tires are repaired. The police authorities follows the bus but it is found out the Vaughn has escaped and only the bus driver is inside. Earlier, Vaughn had got out the bus in police disguise with the help of veterinarian student.
Vaughn calls Jono saying that he is coming for him, but as he arrives at his place, Jono is already is killed by Dog. Later, Dog and Pope takes Vaughn into the same bus, along with Marconi who quickly killed by Pope. Telling where the money is, Vaughn states that Pauline - who reveals that she is the accomplice of Vaughn - is not a pregnant at all but it is actually an inflated bag stick in her stomach and the money is already taken by Pauline as she release from the bus earlier. Pauline then brought the money to paid the bills while Kris - who is already know her style - is sharply looking at her. Vaughn calls is a sort of "trick." Dog is infuriated by Vaughn's strategy and as he about to burn Vaughn up, Pope shoots Dog, killing him. Pope is now concerns his daughter's life and he is letting Vaughn go to visit his daughter once again. Once Vaughn departs, Pope smokes the real cigarette from Dog as the police patrols approaching the bus.