A Tree Grows in Brooklyn begins on a Saturday afternoon in the summer of 1912 in Williamsburg, Brooklyn, where a tree called the Tree of Heaven grows amidst the tenement houses. Francie Nolan is eleven years old, and she and her brother are collecting junk to exchange for pennies. The first child of Katie and Johnny Nolan, Francie loves her neighborhood. This particular Saturday is typical. Francie runs many errands for her mother, makes a daily trip to the library, and spends a relaxing afternoon watching her neighbors from the fire escape. Although the Nolans live in a humble apartment in a run down section of town, they fill their home with warmth and love.

Johnny Nolan, a young Irish man, sings and waits tables for some extra money, but most of the financial support falls to Katie, who works as a janitor in the building in exchange for rent.

The beginning of Book II flashes back to a summer in 1900 when Katie and Johnny first met. Katie and her friend Hildy O'Dair worked in a factory, and Hildy dated a young boy named Johnny Nolan. When Katie first danced with Johnny, she made up her mind to endure any hardship, if she could only spend her life with Johnny. They fell in love and got married within six months. Katie came from a family of strong Austrian women; Johnny was one of many weak and talented men in his family.

The young Johnny and Katie support themselves by working as janitors in a public school, but their lives become more stressful when Katie becomes pregnant. A year after Francie is born, Katie gives birth to a boy, Neeley, who will be her favorite. The stress of living in poverty and having children causes Johnny to become weaker and undependable, while Katie's fighting instinct kicks in. Johnny's drinking problem gets worse and the Nolans move after a binge on his twenty-first birthday brings shame to their family. They love their new apartment on Lorimer Street, and stay until Katie's sister, Sissy, makes some mistakes that shame the family. The house on Grand Street is the third and last of the Nolans's homes in Brooklyn.

Neeley and Francie start school the same year. Francie has anticipated school with great delight, but finds the neighborhood school cruel and mean. Her love for learning is juxtaposed with the cruelties of the teachers and other children. One day, Francie happens upon a beautiful school that she wishes she could attend. Johnny figures out a way for Francie to transfer to this kinder school, where rich children are not favored over poor children like Francie. Although she never makes many friends, school becomes a more positive place for Francie.

Growing up, Francie and Neeley enjoy all the holidays throughout the year. At this point in the book, the flashback ends, and we return to the point at which the book begins. Through many experiences, Francie loses the innocence that marks her character when the book begins. One of these experiences is the tree-throwing ritual. One Christmas, Francie and Neeley participate in an old Brooklyn tree-catching tradition. They remain standing while the biggest tree in the lot is thrown straight at them. Although they are thrilled with the thought of a Christmas tree, the reader understands the cruelty of this ritual, especially when Katie begins to worry that her children do not even know the hardship they live in.

Another loss of innocence occurs with Francie's run-in with a sex offender. Katie is prepared with a gun, and shoots the criminal, and Francie emerges relatively unscathed. Still, this is Francie's first experience with sex of any kind; around this time, Francie also starts her period, and becomes more aware of the social taboos surrounding women's sexuality.

Francie becomes more aware of her father's problems with alcohol. As Francie grows up, Johnny comes home drunk more and more often. Little by little, he becomes more worthless as a breadwinner, and ultimately, his dismissal from the Union puts him over the edge. Also, Katie is pregnant again, which the narrator suggests, makes Johnny all the weaker. Johnny dies Christmas Day, five months before his daughter, Annie Laurie, is born. Her father's death is an important event for Francie's character development. Up till this point, Francie has gone along with her family's Catholic traditions. Now, Francie stops believing in God. She also respected her teachers a great deal, and her English marks especially were important to her. Now, Francie begins to write "sordid" compositions in response to her father's death. Although the teacher disapproves, Francie refuses comply with her order to burn her ugly compositions, and instead burns the flowery compositions that had nothing to do with Francie's life experiences. Burning all of the pretty, flowery compositions is a symbolic loss of innocence for Francie. At the same time, the reader sees that Francie is becoming more aware of her identity, more aware of the kind of writer and person she wants to be.

Although Francie's attitudes toward school and religion may be seen as rebellious, she has not lost her sensitive, caring nature. Francie takes care of her mother in the few days before her delivery, and although she and Katie fight, Francie values her more, knowing the pain and suffering of losing a parent. At the same time, Katie can never replace Johnny for Francie. Sissy accompanies Francie to her school graduation, where Francie finds red roses sent to her from Johnny, who gave Sissy the money for them two years before. At this moment, Francie grieves for all that she has lost--Johnny, and the innocence that disappeared when he died.

Francie and Neeley have to go to work the summer after eighth grade graduation, as Katie cannot support them all. Francie starts working in a factory and then gets a job in a clippings bureau, where she reads papers from all over the country, and learns about the world. One day, she and Neeley proudly present their first week's pay to Katie. Although Francie has a good job, she desperately wants to go to high school. Unfortunately, Katie allows Neeley to go back to school instead of Francie, since they can only afford to send one. The Nolans have more money now with Francie's job, and live more comfortably than they used to. Although Francie never does go to high school, she manages to enroll in college summer classes.

America enters World War I, and the world is changing. Technological advances allow Sissy to give birth to a live baby in a hospital. Francie's first bout with romantic love mirrors the political and economic changes in the world. One day Francie meets a young soldier, Lee Rynor who she falls in love with in 48 hours. Lee goes home and marries his fiancée before going to war, leaving Francie with a broken heart. Eventually, Francie finds that she enjoys the company of Ben Blake a successful boy she met at summer school.

The climax of the novel comes whenSergeant McShane asks Katie to marry him; he is a good man who will make it possible for Laurie to grow up without hardship, and Francie and Neeley to go to college. The Nolans move out of their apartment the day before the wedding while Francie gets ready to leave for college at University of Michigan. And the Tree of Heaven in her yard keeps on growing.