Screwtape is a senior devil and undersecretary of a department in Hell. He is an experienced observer of human psychology who understands the dual physical and spiritual existence of humans. He writes a series of instructional letters to guide a junior tempter in the methods of corrupting a human soul. He embodies a highly administrative approach to spiritual warfare and views all relationships purely in terms of competition and consumption.

Wormwood is a novice tempter on his first assignment to secure a human soul for Hell. He is inexperienced and often clumsy in his methods, focusing on obvious missteps rather than the subtle psychological manipulation his uncle advocates. He reacts to major events in his assigned human's life rather than proactively shaping the human's thoughts and daily habits.

The Patient is an ordinary, middle-class young man living in England at the onset of World War II. He recently converts to Christianity, making him the prime target for a novice devil's assigned mission. He works in civil defense rather than enlisting as a soldier. He experiences standard fluctuations in his religious devotion, social life, and romantic interests, which the devils attempt to exploit through misdirection.

The Enemy is the divine creator and the ultimate opponent of the tempters. He grants humans free will and desires them to choose faith independent of coercion. He views humans as a union of physical and spiritual components. The devils continually misunderstand his motives, unable to comprehend the concept of selfless love.

The Patient's Beloved is a moral, Christian woman who comes from a family of strong but non-fanatical believers. She introduces the young man to her family and their social circle. She possesses a slight tendency to dismiss nonbelievers as silly, an attitude the tempters identify as a potential avenue for spiritual pride.

The Patient's Mother is an older woman who suffers from rheumatism. She shares a household with her son, creating a domestic environment the devils try to weaponize. She demands small, perfectly prepared portions of food, a habit Screwtape identifies as a highly specific gluttony of delicacy.

Our Father is the leader of the devils and the ruler of Hell. He demands absolute loyalty and promotes a philosophy of consumption and competition among his followers. He established the strict hierarchy that governs tempters like Screwtape and Wormwood.