The story follows Jacob Lee (Josh Duhamel), a starship captain who survives a crash landing on the Jovian moon Callisto, only to be captured and incarcerated against his will in a high-security prison.

He is subsequently forced to fight for survival when a mysterious illness sweeps the prison, and gradually learns the dark secrets of his captors.

Gameplay has players exploring a series of levels, gathering resources and collecting data logs while fighting off infected prisoners.

In 2320, Jacob Lee (Josh Duhamel)[4] and Max Barrow (Jeff Schine) are contract freight transporters working for the United Jupiter Company (UJC).

They are recovered by Black Iron Prison security head Captain Leon Ferris (Sam Witwer) and incarcerated on the orders of Warden Duncan Cole (James C. Mathis III).

After an intake process, Jacob awakens to find the prison overrun by hostile "biophages", inmates afflicted with an unknown disease.

Dani appears in a half-track and recovers Elias' memories of Black Iron and decides to assist Jacob as the biophages mutate and become more dangerous.

After Dani fails to find evidence of the UJC illegally smuggling bioweapons in the wreckage of Charon, the two make it to the hangar where they summon a ship.

Jacob is freed by the prison doctor, Dr. Caitlyn Mahler (Louise Barnes), who reveals that Cole is part of a religious sect called Kallipolis, which is attempting to find a way to advance human evolution.

He recovers his own memories showing he was aware that the UJC was using his ship to smuggle larva samples, but he ignored this due to the payments he was receiving.

Jacob puts Dani in the last remaining escape pod along with an alien larva sample, giving her the evidence she needs to expose the UJC's experiments.

Shortly after the end of the main game, Jacob wakes up in the middle of Black Iron, having lost his memories on the outcome of his encounter with Ferris.

Mahler then contacts Jacob and informs him that there is a transport ship they can use to escape the prison, but they must recover her data drives first, as they contain the necessary evidence to expose Cole and Kallipolis’ crimes.

Once the data is finished transmitting, Jacob finally succumbs to his wounds and Mahler accepts her own imminent death as Black Iron collapses The origins of The Callisto Protocol began with the formation of Striking Distance as a studio within PUBG Corporation (now PUBG Studios) in June 2019, helmed by Glen Schofield, who had previously co-created the Dead Space series at Visceral Games.

[7][8] Schofield wanted to keep the game grounded in reality to some degree, and thus selected a potentially human-colonizable location like Callisto as the setting.

Fukuhara plays Dani Nakamura, leader of the resistance group The Outer Way, while Witwer portrayed Leon Ferris, the captain of the Prison Guard.

Schofield stated his intent was "really trying to make the scariest game on next-gen platforms" in the same way that Dead Space had been considered on its release for the PlayStation 3 and Xbox 360.

[6] Striking Distance Studios Chief Technical Officer Mark James said the game was developed with "maximum realism" in mind.

[27] Following the release of The Final Transmission DLC in June 2023, Striking Distance announced in August it would lay off 32 employees to "realign the studio’s priorities.

In the game, the player assumes control of a prison guard in Black Iron who must reach the last escape pod while battling against infected inmates.

[55] Several publications noted that The Callisto Protocol suffered from stuttering and performance issues, primarily affecting the PC version;[56] as a result, the game received "mostly negative" user reviews on Steam upon release.