Although Sula has biological sisters, it is her adopted sister, Nel Wright, whom Morrison places at the center of a story exploring the intricate ties of sisterhood. Nel, who is protected by her refined mother, quickly becomes drawn to the free-spirited Sula: "Their friendship was as intense as it was sudden. They found relief in each other's personality." Sula is captivated by Nel partly because Nel's life is structured and formal, qualities that Sula's chaotic boarding house life lacks. In this way, Morrison presents their friendship as a classic example of opposites attracting. This close bond offers the girls numerous chances to learn about the pleasures and challenges of becoming women: "Joined in mutual admiration they watched each day as though it were a movie arranged for their amusement. The new theme they were now discovering was men." Among the lessons they learn about men is the influence men have over them. As they walk through town on summer days, the men's catcalls make them aware of their own bodies. Sadly, they also confront the violence men can inflict on women, and Sula imparts a crucial lesson to Nel on how to confront this threat. After enduring weeks of harassment from a group of Irish boys, Sula finally grows weary of avoiding their taunts. Demonstrating her own resolve, "she slashed off only the tip of her finger. The four boys stared open mouthed.... 'If I can do that to myself, what you suppose I'll do to you?'" For Sula, resilience in the face of intimidation is essential for adulthood.

The novel continually tests the strength of Sula and Nel's friendship. The first significant test occurs when Sula, in a cruel game, throws a local child into the river, and he never resurfaces. Nel is burdened with keeping Sula's dark secret, which she does for many years, showcasing her loyalty to her adopted sister. As they grow older, their friendship is tested once more when Sula, after being away for decades, has an affair with Nel's husband. Although Nel never forgives Sula for this betrayal, she eventually finds a measure of reconciliation in Sula's final days. Nel tends to some of Sula's needs as she is dying and eventually comes to terms with her friend's misdeeds. Thus, their friendship experiences a full arc, enduring various trials and tribulations over time.