Antagonists in the series include General Hume and his four horsemen, the Knights of Solomon, the Sword of Abraham, and the Grey Witch.

His search leads him to a young woman, Becky Montcrief, who is bound to the Sixth Gun after its former owner is killed.

She gradually learns that the people in the town are unable to leave and are kept so that they can be human sacrifices for the Knights of Solomon.

Becky manages to rescue him, but during their escape, they discover a mosaic mural depicting Drake as a medieval knight.

The two manage to escape from the spirit world, but Becky also unlocks some of the deeper powers of the Sixth Gun, and she feels it is beginning to transform her.

In a flashback, we learn that the Grey Witch serves the Great Wyrms, ancient creatures from the dawn of time.

The first time the humans remade the world, they tried to remake it without the Great Wyrms, but they managed to burrow themselves deep into the roots of creation.

A five-issue spinoff featuring General Hume's horsemen: Bill Sumter, Ben Kinney, Will Arcene, and Silas Hedgepeth.

[11] On July 22, 2011, it was announced that The Sixth Gun would be adapted into a six-part mini-series to air on the SyFy channel,[12] however this did not come to fruition.

In 2013, NBC ordered a pilot based on The Sixth Gun, and Laura Ramsey,[13] W. Earl Brown, Graham McTavish and Aldis Hodge were cast.

[14] Additional cast included Michiel Huisman as Drake Sinclair,[15] Pedro Pascal as Agent Ortega[15] and Elena Satine as Missy Hume.

[16] In 2022, screenwriter Selwyn Seyfu Hinds began developing the series for Universal Content Productions.

[17][18] In 2015, Pinnacle Entertainment Group published the official role-playing game based on The Sixth Gun utilizing the Savage Worlds rules system.