Their Eyes Were Watching God focuses on the experiences of Janie Crawford, a beautiful and determined fair-skinned black woman living in the American South. The novel begins when Janie returns to Eatonville, Florida after having left for a significant amount of time. She is met by the judgmental gossiping of Eatonville's townspeople, whose conversations focus on the fact that Janie had left town with a young man named Tea Cake. Amidst their gossiping, Janie's friend Pheoby Watson stands up for Janie and goes to greet her friend. Janie tells Pheoby her life story, including what happened in the time since she initially left Eatonville, which is the story of the rest of the novel.
Janie spends her childhood being brought up by her grandmother Nanny, a former slave who, despite her controlling nature, has only the best intentions for her granddaughter. Before buying a new home for herself and her granddaughter, Nanny raises Janie in the backyard home of Mr. and Mrs. Washburn, a friendly white couple whom Nanny began working for after she was granted freedom. Nanny wishes for Janie to find improved social standing and financial security in life, and so when she sees Janie kissing a boy she quickly arranges for Janie to marry the wealthy farmer Logan Killicks.
Janie is not content with her marriage to Logan Killicks, but hopefully wishes that she will grow to love Logan. Unfortunately, her hopes are instead met by abuse by Logan, whom she feels treats her as an animal. Thankfully, one day Janie meets the handsome and ambitious Jody Starks, who courts her and eventually encourages her to run away from Logan. Janie complies, they marry, and head off together to Eatonville, Florida.
In Eatonville, Jody seeks political power and entrepreneurial control over the town, becoming both the mayor and the owner of the main store in town. Janie feels love for Jody at the very early stages of their relationship, but ultimately comes to feel stifled by his desire for control and power – especially because he regards Janie as nothing more than an accessory to all of his success.
Jody eventually becomes ill and his treatment of Janie worsens along with his deteriorating health. Finally, Janie speaks up for herself and Jody violently beats her in front of everyone in the store. While Jody is on his deathbed, Janie ceases to be silent, and tells Jody all about how terrible he made and makes her feel. Soon after these conversations, Jody dies.
Following Jody's funeral, Janie does not feel as though she is in a state of mourning, but instead feels free and excited about her life and fulfilling her dreams for the first time in decades. She begins to wear her hair down – not in the mandatory head rag Jody made her wear – and white clothing, to alert potential suitors to her new availability. One day while Janie is working in Jody's former store, a handsome young man named Tea Cake walks in, flirts with Janie and invites her to play checkers with him. Despite Janie's initial ambivalence, she is charmed and spends the rest of the evening with Tea Cake. Because of Tea Cake's younger age and lower social status, the townspeople worry about Janie going out with him, but Janie disregards their judgment and listens to her feelings instead. She and Tea Cake eventually run off together to the Everglades and get married.
Janie and Tea Cake's married life together in the Everglades (or "the muck") is not perfect: he steals money from her, whips her once to assert power over her, and wrestles playfully with another girl in town named Nunkie. A woman in town named Mrs. Turner causes tension in their marriage, too, as she repeatedly tells Janie to leave Tea Cake for her lighter-skinned brother, demonstrating tremendously racist views. That said, Janie feels better with Tea Cake than she had felt with either of her other husbands: Tea Cake treats her as an equal and their marriage is built on authentic love and mutual respect. In the muck, they have many friends and host frequent informal parties at their home.
Their happy life in the muck comes to an end one day a massive hurricane hits the area. During the storm, a rabid dog attacks Tea Cake and infects him with the disease. At first, Tea Cake is unaware of his condition, but quickly worsens and begins to go mad. Janie calls for a doctor who tells her of his disease, but assures the worried Janie that he will send for medicine. Janie realizes, however, that in his ill and manic state, Tea Cake has convinced himself of Janie's infidelity, and has been hiding a loaded pistol beneath his pillow. Janie is forced to kill Tea Cake in order to save her own life. She is brought to court, but found innocent by an all white, male jury after delivering a heartfelt testimony about her true love for Tea Cake.
At the end of the novel, Janie returns to Eatonville – this return is the point at which the novel starts – and concludes her story to Pheoby. Despite her sadness about Tea Cake's death, Janie tells her friend that she is happy to be back, now feeling that she has reached the horizon and has access to her dreams. Tea Cake, Janie feels, is still a presence in her life, as their love provided her with the fulfillment of her desire for a voice and a sense of independence, things she had never known before him.