Peter Highman (Robert Downey, Jr.) is on his way home from Atlanta to Los Angeles to be present at the birth of his first child, a scheduled C-section, with his wife, Sarah. Once on the plane, Peter learns that Ethan Tremblay (Zach Galifianakis), who had accidentally run his car through his door is sitting behind him in first class. After inadvertently using the words terrorist and bomb, Ethan has Peter shot by an air marshal with a rubber bullet. Both Peter and Ethan are forced off the plane before take-off.
After being questioned by security, Peter discovers that he has been placed on the No Fly List and will have to find another way to get to California. After realizing that he had left his wallet on the plane, Peter reluctantly agrees to travel with Ethan, an aspiring actor hoping to make it in Hollywood, to Los Angeles. Ethan is on his way to Hollywood after the funeral of his father, and is carrying his father's ashes in a coffee can on the trip. They are going together by a rental Subaru Impreza 2.5i Hatchback.
After stopping in Birmingham, Alabama to purchase marijuana, Peter and Ethan realize that they collectively only have $60 in cash. Peter decides to have his wife transfer him money. Since he does not have his identification card, Peter has his wife transfer the money in Ethan's assumed last name. Once at Western Union, Ethan recalls the fact that the money has been sent to his stage name and therefore not his real name, Ethan Chase, which is on his only government-issue I.D. The Western Union employee (Danny McBride) doesn't accept Ethan's head shot as proof of ID and declines the transfer. Frustrated and on edge, Peter verbally attacks the man who, even though he is a wheel chair-bound veteran, attacks Peter in retaliation, firmly beating him. Peter is at first contemptuous of Ethan, mocking his acting abilities in a highway rest area bathroom, but begins to soften when Ethan actually breaks down because he misses his father.
After spending the night at the rest stop, Peter waits for Ethan to go to the restroom. Once Ethan is gone, Peter empties the rental car of all Ethan's items and steals that Impreza, leaving Ethan behind. The plan almost works until Peter notices that Ethan's coffee-canned ashes of his father are still in the car. Feeling guilty, Peter returns to the rest stop to and acts like he was always going to come back.
Ethan drives while Peter gets some rest. After a while of driving, Ethan falls asleep at the wheel and the car crashes. At a Dallas hospital, Peter, who has a broken arm and three cracked ribs, is picked up by his friend Darryl (Jamie Foxx). Peter reluctantly decides to take Ethan along. Stopping at Darryl's house, Peter discovers that, nine months ago, Darryl and Sarah spent some time together. This information leads Ethan to accuse Darryl of being the possible father of Sarah and Peter's unborn child.
Peter notices that the coffee Darryl made them tastes funny. After questioning Darryl, he reveals that he used the coffee that Ethan had in his car. Realizing that the 'coffee' is really the ashes of Ethan's father, they spit it out. In a panic while retrieving them from the coffee filter, Ethan accidentally spills his dad's ashes all over the floor. This further saddens him. Peter helps him scoop up the remaining ashes and they leave Darryl's house.
Driving Darryl's Range Rover, Ethan smokes marijuana while Peter is dozing, and the smoke collects in the cabin, intoxicating Peter, as well. The two eventually end up at the Mexican-United States border. Ethan flees from the border checkpoint and leaves Peter to be arrested for possession of narcotics. The narcotics were Peter's pain pills from his hospital visit after the car accident. After being taken into Mexican custody, Peter is broken out by Ethan who steals a border patrol truck in the process.
The duo stop at the Grand Canyon where Ethan spreads his father's ashes. Peter confesses that he did try to leave Ethan back at the rest area. Ethan then decides to also make a confession: he has had Peter's wallet since the plane. Peter attacks Ethan in rage. Sarah calls during the attack to inform Peter that her water has broken. Peter and Ethan immediately begin to rush toward California. Along the way, Ethan accidentally shoots Peter with a gun he had found in the truck's glove compartment. Peter does not stop to receive medical attention for his gun shot wound.
Once at the hospital where Sarah is in labor, Peter and Ethan witness the birth of Rosie, Peter and Sarah's healthy Caucasian baby girl, revealing that it wasn't Darryl's baby. Peter passes out in pain from his wounds. Ethan later recounts to Peter that Ethan had assisted in Rosie's birth by cutting the umbilical cord, something that Peter had allegorically envisioned earlier in the film. The two go their separate ways with the promise that Peter will e-mail Ethan to keep their friendship intact.
At the end of the film, Peter, Sarah, and their new baby girl watch an episode of Two and a Half Men, which Ethan has landed a role in.