Young motorcycle racer Shiro Kazami inadvertently witnesses a murder committed by Destron, a global terrorist organization formed from the remnants of the previous evil group Gel-Shocker. Made a target for elimination, Shiro returns home to find his parents and younger sister brutally murdered by Destron's monstrous soldier, Scissors Jaguar. Before Shiro and a young woman named Junko Tama can also be killed, they are rescued by Takeshi Hongo and Hayato Ichimonji, the cyborg superheroes known respectively as Kamen Rider 1 and Kamen Rider 2.

Driven by grief and a thirst for revenge, Shiro begs the two Riders to surgically convert him into a cyborg like themselves so he can fight Destron. They refuse, knowing the pain and loss of humanity that comes with such a transformation. However, when Shiro later sacrifices his own life to save the Double Riders from a deadly trap set by Destron's leader, they have no choice but to perform the operation to save him. Shiro is reborn as Kamen Rider V3, a more powerful warrior who possesses the techniques of Rider 1 and the physical strength of Rider 2, symbolized by his Double Typhoon belt. Immediately after his birth, the original Riders seemingly perish while averting a nuclear explosion meant to destroy Tokyo, leaving V3 as Japan's sole protector.

The series is set in 1970s Japan, where Destron operates from hidden bases, deploying a relentless series of monster-cyborgs called Inhumanoids to carry out elaborate schemes involving assassinations, sabotage, and mass destruction. V3 is not alone in his mission. He is aided by Tobei Tachibana, a veteran mentor who had previously assisted the first two Riders, and the Boys' Kamen Rider Squad, a network of children led by Junko Tama and her younger brother Shigeru who act as scouts and communicators from their headquarters hidden inside Tachibana's sports shop. The early narrative arc focuses on Shiro mastering his 26 secret powers, often discovering a new technique in the heat of battle when faced with a seemingly unbeatable foe.

The fight against Destron unfolds through a succession of command arcs, each led by a distinct general sent by the mysterious Great Leader. The first and longest-serving commander is Doctor G from Germany, a knight-like strategist who personally leads the attack on V3 after transforming into the Kani Laser monster. He is followed by Baron Fang, a magic-wielding African warlord who commands a clan of fanged beasts, and Archbishop Wing, a Tibetan mystic who employs flying monsters. The final general is Marshal Armor from Mongolia, a heavily armored warrior whose cruelty leads to a pivotal development in the series.

In a significant narrative shift, Marshal Armor falsely accuses Destron scientist Joji Yuki of treason, resulting in Yuki losing his right arm. Yuki escapes and replaces his lost limb with a powerful mechanical arm, becoming the anti-hero Riderman. Initially distrustful of V3 and driven only by a desire to personally destroy Marshal Armor, Riderman gradually becomes a trusted ally. After Riderman ultimately sacrifices his life to save Tokyo from a final Destron plot, Shiro honors him as Kamen Rider Number Four. The series concludes with Shiro confronting the Great Leader of Destron in his headquarters. He unmasks the villain, revealing a skeletal entity with a living heart, and destroys the organization. While Shiro survives the final battle, the Great Leader's voice echoes one last time, hinting at a potential return, as V3 rides off into the sunset to protect the peace he has earned.