A vast UFO descends upon Earth, heralding an invasion by the Vega Alliance and placing humanity under its greatest threat. In response to this looming alien conquest, a refugee from the destroyed planet Fleed emerges as an unlikely savior. This is Duke Fleed, a displaced alien prince who has escaped the destruction of his home world and now lives in Japan under the assumed name Daisuke Umon, having been found with no memories and raised by the scientist Dr. Genzo Umon. Duke is the designated pilot of the colossal and mighty mecha known as Grendizer, a weaponized giant robot that can only be operated by a person with a specific genetic marker.

The narrative of Grendizer U: The Inception modernizes the iconic story of the lost prince burdened with the responsibility of protecting his adopted home from the very empire that obliterated his past. Alongside his best friend and partner, Koji Kabuto, the celebrated pilot of the legendary Mazinger Z, Duke engages in a desperate campaign to liberate Earth from the terror of the Vegan forces. The team is further supported by Koji's girlfriend, Sayaka Yumi, an agent of the Kabuto Zaibatsu, and Duke’s younger sister, Maria Fleed.

The setting is a modernized iteration of the classic universe, where the Photon Power Laboratory, led by Gennosuke Yumi, plays a crucial role in researching the alien technology of Grendizer to upgrade Earth's defensive capabilities. A notable narrative arc is the adaptation of Duke's origin, where he is discovered in the desert by Koji, leading to the restoration of his lost memories as the prince of Fleed and his commitment to the fight against Great King Vega and his army. The manga also includes an original prequel story penned by Tatsuto Higuchi, exploring events not depicted in the anime, which provides deeper insight into the backstory leading up to the Vega Alliance's assault on Earth.