The game will serve as a continuation of the events of Metal Gear Solid V: Ground Zeroes, and will carry over the same tagline of Tactical Espionage Operations first used in Metal Gear Solid: Peace Walker. Set in 1984, the game follows the mercenary leader Venom Snake as he ventures into Africa and Afghanistan during the Soviet war to exact revenge on the people who destroyed his forces during the events of Ground Zeroes.

Metal Gear Solid V: The Phantom Pain is a separated composite of two previously announced Kojima Productions projects, the both of which formed a complex deception. The first was Metal Gear Solid V: Ground Zeroes, originally revealed in a Fox Engine tech demo shown at the Metal Gear 25th Anniversary Party on August 30, 2012. The second was The Phantom Pain, a trailer at the Spike TV Video Game Awards on December 7, 2012, presented as an original title by fictional developer Moby Dick Studios, with the Metal Gear Solid V logo virtually obscured. On March 27, 2013, the true nature of these two projects was revealed at the Game Developers Conference, where Kojima announced that Ground Zeroes serves as a prologue to The Phantom Pain and these two titles form one combined work, to be released separately.