This intense, multi-narrative tale focuses on four interrelated sets of situations and characters, and many events are revealed out of sequence. The following plot summary has been simplified and thus does not reflect the exact sequence of the events on screen.
In a desert in Morocco, Abdullah, a goatherder, buys a .270 Winchester M70 rifle and a box of ammunition from his neighbor Hassan Ibrahim to shoot the jackals that have been preying on his goats. Abdullah gives the rifle to his two young sons, Yussef and Ahmed, and sends them out to tend the herd. Ahmed, the older of the two, criticises Yussef for spying on his sister while she changes her clothes.
Doubtful of the rifle's purported three-kilometer range, they decide to test it out, aiming first at rocks, a moving car on a highway below, and then at a bus carrying Western tourists. Yussef's bullet hits the bus, critically wounding Susan Jones (Cate Blanchett), an American woman from San Diego who is traveling with her husband Richard (Brad Pitt) on vacation. The two boys realize what has happened and flee the scene, hiding the rifle in the hills.
Glimpses of television news programs reveal that the US government considers the shooting a terrorist act and is pressuring the Moroccan government to apprehend the culprits. Having traced the rifle back to Hassan, the Moroccan police descend on his house and roughly question him and his wife until they reveal that the rifle was given to him by a Japanese man, and then sold to Abdullah.
The two boys see the police on the road and confess to their father what they have done, believing at the time that the American woman has died of her wounds. The three flee from their house, retrieving the rifle as they go. The police corner them on the rocky slope of a hill and open fire. After Ahmed is hit in the leg, Yussef returns fire, striking one police officer in the shoulder.
The police continue shooting, hitting Ahmed in the back, possibly fatally injuring him. As his father rages with grief, Yussef surrenders and confesses to the crimes, begging clemency for his family and medical assistance for his brother. The police take him into custody.
This first plotline is interspersed with scenes of Richard and Susan, who came on vacation to Morocco to get away from and mend their own woes. The death of their infant third child, to SIDS, has strained their marriage significantly and they struggle to communicate their frustration, guilt, and blame.
When Susan is shot on the tour bus, Richard orders the bus driver to the nearest village, Tazarine. There, a local veterinarian sews up Susan's wound to stem the loss of blood. Richard contacts the US embassy to request an ambulance. The other tourists wait for some time, but they eventually demand to leave, fearing the heat and that they may be the target of further attacks.
Richard tells the tour group to wait for the ambulance, which never arrives, and eventually the bus leaves without them. The couple stays behind with the bus's tour guide, Anwar, still waiting for transport to a hospital.
Political issues between the US and Morocco prevent quick help, but eventually a helicopter arrives and carries Richard and Susan to a hospital in Casablanca, where she is expected to recover. Richard calls his children's nanny, Amelia, from the hospital, and they agree not to tell the children that Susan has been shot yet. Richard cries as his son tells him about his day at school.
Chieko Wataya is a rebellious, deaf Japanese teenage girl, traumatized by the recent suicide of her mother. She is bitter towards her father, Yasujiro Wataya (綿谷 ヤスジロウ Wataya Yasujirō, Kōji Yakusho) and boys her age, and is sexually frustrated. She starts exhibiting sexually provocative behavior, partly in response to dismissive comments from a member of her volleyball team.
While out with friends, Chieko finds a teenage boy attractive, and following an unsuccessful attempt at socialising, exposes herself to him under a table. Chieko encounters two police detectives who question her about her father. She and her friends take ecstacy pills in public and attend a rave. Chieko sees one of her friends kissing another boy she finds attractive and leaves the party alone.
She invites one of the detectives, Kenji Mamiya back to the high-rise apartment she shares with her father. Wrongly supposing that the detectives are investigating her father's involvement in her mother's suicide, she explains to Mamiya that her father was asleep when her mother jumped off the balcony and that she witnessed this herself.
It turns out the detectives are investigating a hunting trip Yasujiro took in Morocco. Soon after learning this, Chieko approaches Mamiya nude and attempts to seduce him. He resists her approaches but comforts her as she bursts into tears. Before he leaves, Chieko writes him a note, indicating that she does not want him to read it until he is gone.
Leaving the apartment, Mamiya crosses paths with Yasujiro and questions him about the rifle. Yasujiro explains that there was no black market involvement; he gave his rifle as a gift to Hassan Ibrahim, his hunting guide on a trip in Morocco. About to depart, Mamiya offers condolences for the wife's suicide.
Yasujiro, however, is confused by the mention of a balcony and angrily replies: "My wife shot herself in the head. Chieko was the first to find the body. I've explained this to the police many times." After leaving, Mamiya stops at a bar to read Chieko's note. The note's contents are not revealed. Chieko is leaning on the balcony when her father enters the apartment, and the two embrace as she breaks down in tears.
Richard and Susan's Mexican nanny, Amelia (Adriana Barraza), tends to their children, Debbie (Elle Fanning) and Mike (Nathan Gamble), in their San Diego, California home while they are in Morocco. When Amelia learns of Susan's injury, she is forced to take care of the children longer than planned and becomes worried that she will miss her son's wedding.
Unable to secure any other help to care for them, she calls Richard for advice, who tells her that she has to stay with the children. Without his permission, Amelia decides to take the children with her to the wedding in a rural community near Tijuana, Mexico. Her nephew Santiago (Gael García Bernal) offers to take her and the kids to the wedding.
They cross the border uneventfully and the children are soon confronted by the Mexican culture and street scene. The revelry of the wedding extends well into the evening, and the kids enjoy themselves in the festivities. Rather than staying the night in Mexico with the children, Amelia decides to drive back to the States with Santiago.
He has been drinking heavily and the border guards become suspicious of him and the American children in the car. Amelia has passports for all four travelers, but no letter of consent from the children's parents allowing her to take them out of the United States. Intoxicated and worried, Santiago trespasses the border. He soon abandons Amelia and the children in the desert, attempting to lead off the police.
Stranded without food and water, Amelia and the children are forced to spend the night in the desert. Realizing that they will all die if she cannot get help, Amelia leaves the children behind to find someone, ordering them not to move. She eventually finds a U.S. Border Patrol officer.
After he places Amelia under arrest, she and the officer travel back to where she had left the children, but they are not there. Amelia is taken back to a Border Patrol station, where she is eventually informed that the children have been found and that Richard, while outraged, has agreed not to press charges.
However, she is told she will be deported from the US where she has been working illegally. Her plea that she has been in the US for 16 years and has looked after the children (whom she considers 'her children') for their entire lives do not secure lenient treatment. Amelia meets her son on the Mexican side of the Tijuana crossing, still in the red dress she wore for the wedding, now torn and dirty from her time in the desert.