Set in New Orleans in August 2005, the story is narrated by Saint Louis Armstrong Beach, an almost-twelve-year-old boy who lives with his parents in the Tremé neighborhood, a historic area near the French Quarter. Saint divides his life into three parts: the before, the during, and the after. The "during" is Hurricane Katrina. He begins on August 20, one week and two days before the storm, which he calls the absolute best day of his "mostly good before."
That morning, Saint feeds Shadow, a coal-black stray dog who favors him above all others. Saint's father, Valentine (Pops), a chef, refuses to let him own a dog because Pops was bitten by one as a child. Saint grabs his clarinet and heads to the French Quarter to perform for tourists, saving for a $1,200 Leblanc clarinet. His mother, Mercedes, a hospital social worker, reminds him to be home before dark. On his way, he passes MonaLisa Lafayette, his next-door neighbor, whom he calls "Money." A year older, MonaLisa was once his closest friend but stopped speaking to him eight months ago after going through puberty, outgrowing him physically, and joining a clique at her new public school. The break solidified before Christmas, when Saint discovered her hosting an unsupervised party with older teenagers and liquor. MonaLisa blamed him for the missing alcohol, but her mother believed Saint's account and grounded MonaLisa indefinitely.
On Moon Walk, a riverfront promenade near Jackson Square, Saint plays for tourists using techniques taught by his mentor Smokey De Leon, an elderly flute player. Smokey appears for his 79th birthday, and Saint plays "Happy Birthday." Later, Jasmine Jupiter (Jupi), a classmate with a crush on Saint, reads his palm and tells him he has a very short life line, meaning he may not live much longer. The prediction rattles him. That evening, he hears MonaLisa crying in her backyard. Still on lockdown and abandoned by her boyfriend and clique, she tells Saint he is her only friend. They reconcile, and she kisses him on the cheek, sparking a fluttery new feeling. Saint decides it is the best day of his life. The next day at the library, MonaLisa finds a passage confirming that modern palmists no longer believe the life line predicts lifespan, and Saint is relieved.
A tropical storm named Katrina forms near the Bahamas and may shift toward Louisiana. Saint recalls the previous year's grueling evacuation for Hurricane Ivan and prepares by buying a leash and muzzle for Shadow. His plan to hide the dog in MonaLisa's empty garage fails when Shadow barks all night, so he persuades Miz Moran, a stubborn elderly neighbor, to keep the dog. Miz Moran refuses to evacuate, insisting she has survived past hurricanes. MonaLisa comes to say goodbye before her family flies to Los Angeles for a wedding. At the hospital, Saint runs into Smokey, who presents him with the Leblanc clarinet as an early birthday gift, paid in full.
Pops and Saint board up their windows and their neighbors' homes with help from Perry Tiberon and his son Squirrel. Perry once played piano at the Jazz Shack, a French Quarter bar that Saint's late grandfather owned. Shadow escapes Miz Moran's yard but reappears at the Beach front door, and Pops lets the dog sleep inside. Saint names the new clarinet "Smokey." That night, he overhears his parents arguing: Pops wants to leave immediately, but Mama cannot abandon her patients. Katrina is upgraded to Category Three, and President Bush declares a state of emergency. Mama cannot leave the hospital by their agreed time and finally comes home at 2:00 A.M.
Sunday morning, Mayor Nagin orders mandatory evacuation as Katrina becomes a catastrophic Category Five hurricane aimed directly at New Orleans. The Superdome, the city's massive sports arena, is designated a refuge of last resort. Mama still cannot leave the hospital, so Pops' brother, Uncle Hugo, arrives to drive Saint to their grandmother's house in Baton Rouge. As Saint hands Shadow's leash to Pops, the dog yanks free and bolts. Sobbing, Saint is forced into Hugo's packed car with his aunt Vi and three cousins.
At a gas station a few miles outside the city, Saint escapes while the family uses the restroom, grabs his duffel bag, and sprints back toward New Orleans, knowing Hugo cannot turn around on the one-way outbound interstates. Back in Tremé, he searches for Shadow block by block. He finds Miz Moran on her porch with a baseball bat, having hidden from her daughter to avoid evacuation. She lets him call Mama briefly, then he falls asleep on her sofa. Shadow's barking wakes him before dawn, and he lets the dog inside as the hurricane strikes. The power fails, the wind howls, and water begins pouring through the floor. The levees have broken.
Saint, Miz Moran, and Shadow retreat to her attic, stocked with supplies including water, food, flares, and an inflatable boat. Saint discovers Miz Moran forgot her insulin for her diabetes, so he wades downstairs through the flooded house to retrieve it from the submerged refrigerator. Conditions deteriorate: Shadow punctures the inflatable boat, the fan burns out, and Miz Moran's insulin supply dwindles. She reveals she has had three heart attacks and carries nitroglycerin pills. Saint charges the boarded-up attic window headfirst, knocking the plywood free. From the balcony, they see water stretching to the horizon. Hours later, a helicopter descends, but there is room for only one more person. Miz Moran insists they take Saint, then collapses unconscious. Saint screams that she needs insulin, and the rescuer airlifts her, leaving Saint and Shadow behind.
While waiting, Saint dreams of his late grandfather, King Daddy Saint, leading a Mardi Gras parade alongside the legendary Louis Armstrong. King Daddy Saint touches Saint's chest and tells him they are "nowheres near ready" for him, answering Jupi's life-line prediction. He warns Saint to avoid the Superdome and head to the Jazz Shack instead. A second helicopter arrives, and Saint refuses to board without Shadow. The helicopter delivers him to the Superdome, where he sees chaos and crowds. Heeding his dream, he yanks Shadow's leash and heads for the French Quarter, trudging through thigh-high floodwater. He reaches the Jazz Shack, where Perry and Squirrel and a group of musicians are sheltering. They give him food, dry clothes, and a cot.
The next morning, Shadow barks at the Jazz Shack door. Perry opens it, and Saint sees Mama and Pops standing behind the dog, accompanied by their friend Mose, a police officer. They had found the rescue crew that airlifted Saint from Miz Moran's roof and learned he was taken to the Superdome. On their way there, Shadow appeared and led them to the Jazz Shack. As the family departs, Pops calls the dog "Shadow" by name for the first time, signaling his acceptance of the animal.
More than 216 hours after the evacuation order, the Beach family is at their grandmother's house in Baton Rouge. Mama locates Miz Moran, who is alive and recovering in a hospital in Atlanta. Saint goes outside with Shadow and his Leblanc clarinet. He wonders whether he will ever see Jupi, the Tiberons, Smokey, or MonaLisa again. He reflects that even if New Orleans is "over," no one can take the city away, because it lives inside him. He puts the clarinet to his lips and plays the blues.