In a sun-baked Arizona bar, Steven Williams portrays Fred "Rabbit" Smith, a witness who's suddenly handcuffed by two federal marshals, Lou Diamond Phillips as Jack La Roca and Lori Petty as Steph, with orders to spirit Rabbit all the way to Los Angeles to testify against mobster Benny "The Buzzsaw" Buffalino. A deadly pursuit follows, as Sergei and his team of hitmen close in, forcing the marshals to summon a backup car crew that includes Nick, Mary, P.T., and Joe—the four charged with fending off the attackers until they reach safety. Nick is played by Alex McArthur, Mary by Mercedes Colon, P.T. by Dale Midkiff, and Joe by Rob Roy Fitzgerald. Together the group fights through the ambush, killing almost every pursuer but Sergei and continuing their tense trek toward Los Angeles.
As they push north, they learn of Route 666, a condemned strip running parallel to the famous Route 66 near the California border. The road’s grim history—built on a prison road crew accident—echoes in Jack’s memory, triggering a series of flashbacks about his own childhood: he was born nearby, his mother died when he was six, and his relationship with his father is only a memory.
On the highway’s edge, a county deputy named Gil Conaway spots the convoy and calls for backup, sparking a clash with the marshals. Jack shows his badge and Gil retreats, but not before the road reveals its strangest secret: a cemetery, and later the graves of four notorious 1960s killers—Miles Hackman, Frank Slater, Steve Pikowski, and John La Roca—whose spectral presence begins to weave into the night. The fate of Rabbit’s party grows darker when a moment of betrayal unfolds: Mary and Nick leave Joe to watch Rabbit, Sergei appears and shoots at Rabbit and Joe, and Joe is killed not by Sergei but by the undead remnants of the earlier killers.
The haunting continues as Nick drifts asleep in a car and is killed by Slater. Rabbit, handcuffed to a pole, escapes as Pikowski attacks, and he discovers the road’s rule: the undead can travel only on Route 666, surfacing from underground and moving along concrete. In a frantic turn, Jack dials 911 to reach Sheriff Conaway for help, giving him the Los Angeles marshal’s number and urging backup to reach them before more zombies arrive.
Flashbacks deepen the history: Jack sees his father, John La Roca, and the other notorious convicts at work on the road—Hackman, Slater, and Pikowski—while Hackman briefly escapes before a police officer forces them to dig another hole. In the present, Sheriff Conaway and his deputies close in, cornering Jack and Steph and their captured ally Gil inside a pickup area. Conaway murders Mary to force P.T. to reveal Jack’s location, and a violent struggle erupts as Conaway’s crew corner the survivors. The group frees Gil only to have the four zombies close in, killing Gil and leaving the survivors on the run.
A climactic confrontation unfolds when Jack, Steph, Rabbit, and Conaway collide with the resurrected convicts. The zombies pin Jack down, and a poignant revelation emerges when Jack admits to his father that he is his son; John La Roca then turns the tide, killing the last of the undead and lifting the road’s curse. The vengeful Sheriff Conaway reappears in the chaos, yet is outmatched as a ghostly road roller ends his pursuit. With the curse broken, Jack, Steph, and Rabbit walk toward Los Angeles, stepping beyond Route 666 into an uncertain dawn of freedom and a long, eerie road behind them.