Ace Combat 6 covers the war between the Republic of Emmeria and the Federal Republic of Estovakia on the Anean continent, north of Yuktobania. It begins with the invasion of the Emmerian capital, Gracemeria, by the Estovakian Air Force on August 30th, 2015. Players take on the role of an Emmerian pilot and squadron leader Garuda 1 who has the callsign "Talisman". The player's wingman is Garuda 2 who goes by the callsign "Shamrock", and will fight alongside Talisman throughout the entire game. Both characters are assigned to the Garuda team of the Emmerian Air Force's 28th Tactical Fighter Squadron.

The cut scenes between levels depict a few stories and how the player's actions influence their own. One story is of a mother, Melissa Herman, who became a refugee after the first battle. She went on a journey to save her daughter, Matilda, whom she believed died early in the game. On the way she meets an Estovakian woman, Ludmilla, who is heading to Gracemeria to be reunited with her boyfriend, Toscha Mijasik, a member of the antagonistic Strigon Team. Another story is about Lt. Col. Victor Voychek, an Estovakian soldier. He was the leader of the Strigon team until he became injured during the Estovakians' conquest of Gracemeria. There are also smaller plot lines in the cutscenes depicting Emmerian Army Sgt. Louis McKnight and his tank crew and of the new Strigon Team Leader, Ilya Pasternak, who is Mijasik's flight lead.