Assassin's Creed III is a historical open world action-adventure game with a focus on stealth. Despite the numbering it is the fifth main game in the series and a direct sequel to the previous game Assassin's Creed: Revelations. After the events of the previous game the series' protagonist Desmond Miles travels with father William and the two companions Rebecca and Shaun to a cave in New York where they have located a temple made by the members of the First Civilization. Using the Apple of Eden, Desmond is able to activate a large part of the equipment. It was built to help protect Earth against a solar flare that threatens to wipe out the planet. Desmond falls into a fugue state however and is brought into Animus, the virtual reality machine that allows him to experience his ancestral memories. He will use Animus to find the answers for the First Civilization's warning, and the threat posed by the Knight Templars and their modern day organization Abstergo Industries.

From that initial modern day environment the rest of the game is largely set in Colonial America, before, during and after the American Revolution from 1753 to 1783. The main protagonist for this game is Ratonhnhake:ton (Connor), a member of the Mohawk tribe. He is only introduced after a substantial portion of the game as it first follows his father, the Londoner Haytham Kenway, who travels to America after killing an Assassin in the London Opera. The player experiences the gameplay of the opera killing, the journey on the boat, and the arrival in Boston. Haytham is a Templar. He stole a key in the Opera and works together with five men loyal to his cause to locate a storehouse the medallion key is for. As he also gets involved in the local events, he meets the Mohawk woman Kaniehti:io (Ziio) and she gives birth to Connor. The game then offers 30 years of Connor's life to play, from his childhood with the Mohawk tribe through the training to become an Assassin after his village is attacked by the Templars under the command of his father. The Assassin-Templar war then becomes part of the American Revolution.