Ren Homura moves back to his hometown of Kaminohara with his family, but he cannot remember much about the time he spent there, only experiencing vague flashbacks. After his cell phone breaks and is sent for repairs, he retrieves it to find a mysterious game called Monster Strike mysteriously installed. When he opens the app, his life changes forever as a strange man attacks him, forcing him into a real-life game where monsters are summoned from the phone to battle. Trapped on a stage designated for combat, Ren manages to summon a small, seemingly useless dragon named Oragon, who becomes his partner. With help from his classmate Aoi Mizusawa and an alter ego awakened by his own lost memories, Ren defeats his attacker, freeing the man from an evil entity's control.

The story takes place in a version of the real world where most junior high students in Kaminohara play Monster Strike, and the town has stadiums where the game is played using advanced holograms that make the battles appear real. The main characters include Ren Homura, the protagonist; Aoi Mizusawa, a classmate whose signature monsters include Oragon, Fenrir X, and Ryoma the Visionary; Akira Kagetsuki, who initially refuses to play on a team because Ren is nothing like their former fourth member Haruma; and Minami Wakaba, who becomes possessed by the same evil presence that controlled others who attacked Ren and Aoi. Oragon provides comic relief as a tiny dragon of questionable usefulness.

As the series progresses, the group reunites as a team to participate in Monster Strike leagues, but the stakes escalate when monsters begin manifesting in real life outside the game. The first season consists of 51 episodes, with a second season titled Monster Strike The Animation: The Fading Cosmos premiering later, introducing a new American transfer student named Mana as the group deals with monsters causing problems in the real world.

The narrative expands beyond the initial high school setting into larger celestial conflicts. A subsequent series shifts focus to the Angelic Guard, who call the heavens their home and are tasked with collecting orbs scattered across the world. Lucifer, a rebellious leader of the Angelic Guard said to wield power rivaling the Almighty, carries out her duty alongside Uriel, another leader. The Holy Magistrate Keter tells Uriel of Lucifer's planned rebellion, leading Uriel to discover the accusations may be connected to an event that once threatened to shatter the heavens.

The story follows multiple arcs featuring different historical and mythological figures. These include King Arthur portrayed as a blonde woman, King Solomon's granddaughter who carries the same name, and Noah depicted as a shounen protagonist. Each arc explores themes of redemption, rivalry, and the struggle against villainous forces. The series culminates in an ensemble finale where characters from across the various storylines unite for a final confrontation against a generic evil threat.