Quicksand tells the story of Helga Crane, a young woman of biracial parentage who experiences discrimination in America in the early 20th century. She and her Danish mother are deserted by her African-American father shortly after her birth. The early portion of the book portrays Helga as a young teacher at Naxos, a boarding school in the American South established for the purpose of educating young Negro children. The book relies heavily upon an increasingly discontent internal dialogue on the part of the protagonist, and she uses this to rationalize her abrupt departure from what she perceives as the racist atmosphere of the school, as well as the unexpected breaking of her engagement to James Vayle. She submits her resignation personally to the young principal, Dr. Robert Anderson, to whom she is attracted.

She travels by segregated train to Chicago for the purpose of securing a loan from her white uncle; however, she is rebuffed by his wife and maid. This event introduces a cycle of social isolation, anger and despair that characterizes Helga. While residing at the YWCA, she ultimately secures employment as an assistant to a wealthy widow, Mrs. Hayes-Rore, who brings Helga to Harlem. Here, Helga is in her true element as she resides in the luxurious townhouse of Anne Gray, a young widow. Ultimately, Helga comes to resent the people of color by whom she is surrounded and finds her generous hostess to be hypocritical and shallow.

An unexpected letter from her uncle, Peter, contains the funds that allow her to exit Harlem and travel to Denmark to reside with her maternal aunt and uncle. She enjoys the material wealth and attention that is afforded her there, as well as the hiatus from the prejudice she experienced in America. Helga meets a famous portrait artist, Axel Olsen, who eventually proposes marriage to her. Helga becomes repulsed by Olsen and angered by his proposal; much to the chagrin of her family, she rejects the offer. Helga returns to America to attend the wedding of Anne Gray and Robert Anderson. Initially happy in Harlem, she becomes irritable and restless again, particularly after a brief but humiliating romantic interlude with Dr. Robert Anderson.

Depressed and isolated once more, Helga wanders the streets of Harlem and happens upon a revival meeting. She is emotionally vulnerable and decides to embrace religion. Her conversion is so immediate and extreme that she seduces and marries the naïve minister of the church, Mr. Rev. Pleasant Green. They relocate to rural Alabama to minister to a small congregation. Helga’s initial zeal for helping the poor women of the community is replaced by exhaustion and illness as she gives birth four times over a short period. As she recovers from the birth of her last child, who dies in early infancy, Helga reverts to a familiar emotional pattern. She comes to despise Pleasant and plans her escape from Alabama, only to discover that she is pregnant for the fifth time.