In the 1995 anime series Street Fighter II V, Guile is portrayed as a Master Sergeant in the United States Air Force, a man who takes immense pride in his military service and dedicates the majority of his time to intense physical training. His character is defined by a stern, no-nonsense exterior that masks a deep reservoir of intensity and pride, which becomes evident when he first crosses paths with the series' protagonists, Ryu and Ken. This initial encounter occurs in a bar, where a dispute involving Guile's fellow servicemen leads to a fight. Guile steps in and soundly defeats Ryu with little apparent effort, demonstrating a level of power that surpasses the young martial artist. Not content to let the matter rest, Ken later challenges Guile to a rematch at an air force base. Despite suffering from a severe hangover at the time, Guile still manages to defeat Ken, solidifying his position as a formidable and almost insurmountable obstacle for the pair.

This defeat serves as a critical turning point for Ryu and Ken. Guile, through his sheer strength and unwavering discipline, inadvertently becomes a source of motivation for them. Their loss at his hands forces them to recognize their own arrogance and lack of experience, inspiring them to embark on a journey around the world to test and improve their skills against various opponents. Later in the series, when Ryu, Ken, and Chun-Li are captured by the criminal organization Shadaloo, Guile is recruited by Ken's father to assist in the rescue mission. He is joined by his closest friend and fellow soldier, Charlie, who is referred to as Nash in some versions of the story. Guile's primary motivation throughout the latter part of the series is a sense of duty and loyalty, both to his friends and to the mission at hand. He infiltrates Bison's base and confronts the massive Russian wrestler Zangief, managing to knock him out in a display of his superior combat skills.

The key relationships in Guile's life are central to his role in the story. His deep bond with his comrade Charlie is a defining trait, and he fights alongside him against the forces of Shadaloo. However, the narrative tragically prevents Guile from saving Charlie from a direct confrontation with the series' antagonist, M. Bison. This loss fuels his determination, but he is also forced into another devastating emotional conflict. Bison unleashes a brainwashed Chun-Li against Guile, pitting him against a friend and ally. Guile is forced to fight her to defend himself, a situation that only ends when Bison's defeat breaks his hold over her mind. Guile's development in the series is not focused on a change in his own fighting philosophy, but rather on his function as a catalyst for growth in others. He begins as an adversary who humbles the protagonists and ends as a respected, battle-hardened ally who shows admiration for their resilience when they emerge unharmed from the final battle.

In terms of fighting ability, Guile is depicted as a master of a unique, sound-based combat style. His signature techniques are the Sonic Boom, an energy projectile he fires by cupping his hands together, and the Flash Kick, a powerful jumping somersault kick performed in reverse. These moves require precise timing and positioning, reflecting his patient and defensive fighting philosophy. His combat skills are such that he easily outclasses both Ryu and Ken early in their journey, and later, he is able to defeat the powerful grappler Zangief, solidifying his status as one of the most capable and technically skilled fighters in the series.