Like many of Capote's young male protagonists, Joel Harrison Knox is essentially an orphan. Alienated from his schoolmates because of his delicate—almost effeminate—appearance, he decides he resembles Little Kay in "The Snow Queen," and because his life seems to lack emotional warmth, he wonders if he too has been spirited off to a frozen palace. He feels comfortable only when he is sharing his lunch with a Negro stevedore or when Mr. Mystery selects him as a volunteer during the magic show. Further isolated by the death of his mother, Joel has been taken in by his aunt, Ellen Kendall, but he is an outsider in this household too. Even though the family treats him well, he resents them and often is cruel, especially to his deaf cousin, Louise. When his father, Ed Samson, invites Joel to come and live with him at Skully's Landing, the naive boy eagerly anticipates finally meeting the dashing figure who has been the subject of his fantasies. For most of the novel, however, Joel finds himself an outsider at Skully's Landing, and he writes several letters asking Ellen to come and rescue him from his new "family": a paralyzed father, a stepmother whose behavior is bizarre at best, and her drag queen cousin, Randolph. Only when his abortive escape attempt ends in his serious illness, and Randolph nurses him back to health, does Joel begin to realize that now he has become a necessary part of the household at Skully's Landing.

In Other Voices, Other Rooms a major theme is coming of age. When Joel leaves New Orleans for Skully's Landing, he is essentially a child, but at the novel's end, he senses his own maturation and looks back with detachment on the child he used to be. Finally he can acknowledge the sexual attraction he feels for Randolph. Moreover, he realizes that his is the stronger personality and that only he can provide the reassurance Randolph needs —that everything will be all right. Their excursion to the Cloud Hotel reveals Randolph's total helplessness, but upon their return, Joel also realizes that actually he is still alienated, not only from his "bloodkin," but now also from the misfits who have been his only companions.

Like Joel and Randolph, most of the characters in this novel lack a sense of security, but often, as they desperately seek to escape imagined dangers, they encounter real dangers far more serious. For example, Missouri Fever wants to flee Skully's Landing before Keg Brown is released from prison and returns to cut her throat. Finally freed by her grandfather's death, she begins walking to Washington, only to be gang-raped. She then returns to Skully's Landing. Likewise Idabel Thompkins runs away from the father and sister she believes will destroy her individuality, only to fall under the spell of Miss Wisteria, the carnival midget, who appears to have sexual designs on her.

Throughout the novel, Capote emphasizes the interrelated themes of death and change. In each of the three sections, a death significantly changes Joel's world. In Part One, Joel's mother dies and he leaves the family he has always known to go and live with his father. Not only does he travel on his own from New Orleans to Skully's Landing, but he finds himself in a household dominated by physical and psychological weakness. He must determine for himself what is reality and what is delusion, but, at the same time, he feels completely alone and defenseless. In Part Two, Jesus Fever dies. Because of Jesus' great age, Joel had come to consider him almost immortal, but the old man's death reinforces the concept of mutability. Moreover, when Missouri no longer has to care for her grandfather, she leaves Skully's Landing, and Joel believes he has lost his only ally within the household. For that reason he agrees to run away with Idabel. The death in Part Three is that of John Brown, the mule. When Joel and Randolph leave the Cloud Hotel, Joel allows Randolph to lead him so that he can keep his eyes shut and thus avoid looking at the body of John Brown, but this represents the last vestige of his childhood. Without the mule, Joel and Randolph must walk back to Skully's Landing, and Joel learns that Randolph can merely travel in a circle, which reflects "the zero of his nothingness."

When Joel directs their journey home, he assumes the adult role relinquished by Randolph. At the novel's end, Joel appears to have become the head of the household, as he rejects "bloodkin" and moves toward the mysterious "woman" beckoning to him from Randolph's window.