In 1912, in Brooklyn, there is a tree between apartment buildings called the Tree of Heaven. Francie Nolan, 11, and her younger brother enjoy living in the city, they like they're neighborhood, and they entertain themselves by finding money dropped on the ground. Francie's mother is Katie, and her father is Johnny, a waiter and performer who often sings for extra tips. Katie works as a janitor at the apartments, though, because Johnny can't earn enough to support them fully.
After this opening, the book describes through flashback how Katie and Johnny met, working for a factory. Katie knew Johnny because Johnny was dating her friend Hildy O'Dair. She fell for him quickly and begged fate to bring them together, no matter what hardship might befall them. We then cut forward in time; the couple is together, living in a low-income apartment that they work as janitors. Katie becomes pregnant.
Now with the stress of Francie and Neeley, her little brother, the family's poverty becomes unmanageable. Johnny begins to show signs of waywardness, picking up a nasty drinking habit, and triggering a new side of Katie that he doesn't know, a side of her that is dead serious about supporting the children. Johnny turns 21 and embarrasses himself overdrinking at his own party. They move to Lorimer Street with Katie's sister until Katie's sister's life spiral in its own way. They then move to the house from the beginning of the novel, the house of Grand Street.
Back in the present, Neeley and Francie are starting school. Francie's optimism is disappointed when she sees how mean her classmates can be. Francie finds a school she'd rather attend, but it's typically reserved for the wealthy. Johnny manages to get her admitted, though, and although she's too poor to make friends, people aren't mean to her like they were at the other school. Francie and Neeley make it to winter, and their family stands to catch a thrown Christmas tree (a ritual built around the fact that they are too poor to buy a tree).
One day, a sex offender tries to molest or rape Francie, but Katie is ready for the attack, and she pulls a gun, killing the rapist. Francie is shocked by sex, by the man's defenseless behavior, and by the sudden death—all overwhelming in their own right. Not long afterward, she starts her period. At home, thinks are getting more serious with Johnny's drinking problem. When news comes that Katie is pregnant with her third, Johnny's binge drinking leaves him dead on Christmas Day. A few months later, Annie Laurie is born.
Francie was raised an Irish Catholic, but in the wake of her father's death, the preteen decides she doesn't believe in God. At school, the teachers report that Francie has begun replacing her typically adorable poetry with scathing, dark, moody writings. They beg her to stop, but she will not. Together, through time, Francie begins working through forgiving her father's selfishness, but she misses him dearly. She and her mom deal with the pain together, but Katie is no replacement for Johnny.
Francie is an adult now. She dates Lee Rynor, a soldier, and loves him, but when he gets his orders to be deployed into combat, he marries someone else. She is heartbroken, but fortunately Katie has better luck with the gents. Sergeant McShane proposes to her, allowing the family to become supported again financially. Francie and Neeley will both attend college. Francie chooses the University of Michigan. At the end of the novel, we learn that the Tree of Heaven is still thriving.