Hephaestion is a central figure in the anime Reign: The Conqueror, known in Japanese as Alexander Senki. As the closest companion to Alexander the Great, he serves as a general, advisor, and constant presence throughout the Macedonian king's ambitious campaign to conquer the known world. Hephaestion is portrayed as a young man of Macedonian noble birth, having grown up alongside Prince Alexander. From an early age, he served as a page to the prince, and both were pupils of the renowned philosopher Aristotle. This shared upbringing forged a deep and enduring bond between them, establishing Hephaestion as Alexander's most trusted confidant and a key figure within his inner circle as soon as Alexander assumed the throne following his father's assassination.

In terms of personality, Hephaestion is depicted as a quiet, reserved, and intensely focused individual. Unlike the more flamboyant and larger-than-life Alexander, he is rarely the center of attention by his own will and is far more comfortable operating as a support from the shadows. His demeanor is often serious and contemplative, and he possesses a dry wit that reflects the more solemn side of his king. He is an intellectual at heart, viewing warfare as a grim necessity rather than a source of glory or entertainment. While he is a capable strategist, his primary driving force is not ambition for himself but his unwavering loyalty and devotion to Alexander. This loyalty is so profound that it overrides his own preferences and even his principles, making his desire to help and protect Alexander the engine behind nearly all of his actions. He is not particularly fond of displaying his emotions, often keeping his true feelings closely guarded and shifting between expressions of worry and practiced indifference in social situations.

Hephaestion's motivations are singularly focused on Alexander and his happiness. His purpose in life is to support his king in achieving his dreams, and he constantly asks himself whether his actions will help Alexander or bring him pleasure. This drive leads him to study military strategy, master the lyre for Alexander's enjoyment, and position himself as an indispensable advisor and protector. This devotion, however, is also his fatal flaw. It surpasses both logic and emotion, leading him to support Alexander even when prophecies suggest the king will destroy the world. He is not only ready to die for a cause he may know to be wrong but is also willing to sacrifice the entire world if it means remaining loyal to Alexander.

Within the story of Reign: The Conqueror, Hephaestion's role is multifaceted. He is one of Alexander's primary generals, commanding a portion of the army during their conquests. His role extends beyond the battlefield, however, as he frequently acts as an advisor, a bodyguard, and the keeper of Alexander's confidence. He is often shown knowing Alexander's whereabouts and is entrusted with personal tasks, such as watching over the king's sword. His importance is such that he is one of the few people whose loyalty is never questioned, even when the army begins to search for traitors within its ranks. In one notable event, Hephaestion single-handedly stops an assassination attempt on Alexander during the king's wedding to the Persian princess Roxanne, killing a dancer sent by a cult to poison his king.

The key relationship in Hephaestion's life is, unequivocally, his bond with Alexander. The series heavily implies a deep, intimate connection between them that transcends simple friendship. This relationship is the core of his character, and his actions are all filtered through his loyalty to the king. While Hephaestion himself is reluctant to put his feelings into words, their closeness is acknowledged by others, such as the philosopher Aristotle, who is noted to have said they shared a bond of one soul dwelling in two bodies. Other significant relationships are less deeply explored but include his role as a general among other Macedonian officers and his service to Alexander's mother, Olympias, who had a hand in his upbringing.

Hephaestion undergoes relatively little change in his core beliefs throughout the series; his development is more of a deepening of his existing traits. As the campaign progresses and Alexander’s ambitions grow more extreme, Hephaestion’s devotion becomes increasingly absolute. He does not attempt to temper Alexander’s course but instead doubles down on his support, even as the potential for destruction becomes more apparent. This unwavering commitment ultimately leads to his tragic end, as he dies taking a blow that was meant for Alexander, a direct consequence of his all-consuming devotion.

In terms of notable abilities, Hephaestion is not portrayed as the most powerful warrior in the Macedonian army, a fact that sets him apart from the more traditional generals. Instead, his skills are more refined and intellectual. He is an adept strategist and planner, valued more for his mind than his brute force. As a combatant, he relies on agility and grace rather than heavy weapons, often fighting with throwing knives and using gymnastic-like movements. This elegant fighting style complements his identity as an artist; he is a highly skilled musician, specifically a player of the lyre, a talent for which he is compared to famous musicians of old. This artistic side provides a stark contrast to the brutal world of conquest and is something he uses to please Alexander and provide entertainment in the camp. His physical appearance in the series is also distinctive, with notable design choices including blue hair, a common stylistic element in the show's unique aesthetic.