Fast-paced and fiery, this multi-layered crime thriller follows Luke Vaughn, a man working in a Southern casino run by 'The Pope', has a sick daughter in a hospital. The money he earns is not enough to pay the medical bills. Vaughn must pay for her treatment by Friday and desperately needs $300,000, but Pope refuses his plea for a loan and instead fires him, with his right hand man 'Dog' beating up Vaughn when he objects.
Vaughn is approached by Cox and agrees to rob the money, which the casino is laundering for the mob. After a $3 million heist, the masked thieves are intercepted by Dog's henchmen. A gun battle ensues, wounding one of the thieves. They are forced to hijack a city bus, number 657, after their getaway driver escapes in terror. Police Officer Kris Bajos is parked a half block from the bus stop. Kris hears the gunshots coming from the bus and pursues in her police vehicle.
Pope orders Dog to retrieve the money, resulting in Dog going on a murderous rampage to learn who all the thieves are, killing multiple people. While Pope is unsympathetic to Vaughn's situation, he is alienated from his own daughter, Sydney, so he orders Dog to leave Vaughn's sick daughter alone.
As the thieves commandeer the bus from its driver, Bernie, they take off the masks and Dog's henchmen identify them. As Kris chases the bus, Cox nearly shoots her. The rest of the police cars pursue and post roadblocks. To make Kris negotiate with them, Vaughn writes a passenger's phone number on a bus window. Vaughn warns her that Cox will kill some of the passengers, including the pregnant Pauline, if Kris doesn't order the police to clear the roadblocks. Kris rams the roadblock, allowing the bus to enter the interstate.
The next morning, the wounded thief is dying. Vaughn asks one of the passengers, a veterinarian student, to take care of him. Cox orders Bernie to head to Galveston, Texas; unfortunately, the bus is running low on fuel, so Vaughn calls for a fuel tanker.
Detective Marconi joins forces with Kris when she is about to be relieved from duty. Marconi monitors the bus via a police helicopter. Cox makes a call to Jono, an old man who aided them in planning the robbery, informing Jono that they have the money and are on the way. While refuelling, Vaughn allows two hostages (Pauline and a young boy) to be released. Kris discovers that Vaughn pulled the robbery because of his ill daughter. Meanwhile, Dog learns the location of Jono through a police radio scanner.
With the wounded thief suffering blood loss, Vaughn calls Marconi to come aboard the bus with a medical kit. He boards and takes a call from Pope, tossing the phone to Vaughn, revealing Marconi's affiliation with Pope. Shortly thereafter, a SWAT team attacks the bus and pops the bus tire, causing it to crash near a bridge. Most of the passengers receive minor injuries.
With police surrounding the bus, Cox holds Bernie hostage in front of the cops and on live TV. Bernie is presumably shot dead by Cox, but it is revealed that Vaughn shot his partner Cox instead, saving Bernie. Vaughn receives a call from his daughter saying that the money has arrived to pay the hospital bills. Vaughn releases all the hostages and the bus departs once the tires are repaired. The police authorities follow the bus but find out Vaughn has escaped and only Bernie is inside.
Vaughn arrives at Jono's, but finds Dog has killed him. Dog takes Vaugn prisoner by knocking him out with a shot of rock salt from a shotgun and they are joined by Pope and Marconi back on the bus, though Pope soon kills Marconi. Vaughn shows them where the remaining $2.7 million is hidden on the bus, then explains that Pauline was not a pregnant passenger but is actually his sister, who hid the missing $300,000 in her 'tummy'. Kris had deduced what Pauline was doing and did not stop her from paying the medical bill.
Dog is infuriated and is about to burn Vaughn alive, threatening to go after Vaughn's daughter next, when Pope shoots Dog dead. A grateful Vaughn is allowed to get away.