Unlike other games in the series in which the events are narrated from a single perspective, Ace Combat 6's story is interlaced with cutscenes depicting numerous side-stories told by various figures on both sides of the war, describing their personal struggles and opinions regarding the conflict as it progresses.

While gameplay elements from previous titles persist in Ace Combat 6, the game's main campaign features more extensively detailed missions.

[1] As with other games in the series, Ace Combat 6 places players in the role of a fighter pilot, tasked with destroying foes both in the air and on the ground.

The game's main controls are simplified as part of the series' design as an arcade flight game, with players given access to not only a wide variety of licensed fighter jets, but also access to a variety of weapons; alongside autocannons and missiles, planes can be equipped with one of several special weapons for use in engagements, including radar-guided missiles, bombs, and rocket launchers, amongst others.

While the player can lock on to foes and switch between targets (dependent on weapon being used), the in-game HUD provides feedback on ammo amounts, damage to the craft, speed and altitude, offers a radar that can be tuned to different zoom levels or display a full map of the combat zone, and provide information on the amount of time left during a playthrough, and the player's current score.

16 years prior, an asteroid impact event devastated Estovakia and left it economically and politically unstable, but Emmeria was unscathed and continued to thrive.

Other main characters seen in cutscenes include Lt. Col. Victor Voychek, an Estovakian ace pilot who is reassigned to an intelligence officer role in Emmeria after being shot down by Garuda Team; Melissa Herman, an Emmerian civilian who attempts to find her missing daughter Matilda; Ludmila Tolstaya, an Estovakian civilian who travels with Melissa, seeking to be reunited with her fiancé Toscha, an Estovakian fighter pilot; and "Serval", an Emmerian tank unit consisting of Emmerian soldiers Louis McKnight, Donnie Torch, and Kevin Hobsbawm, who sneak behind enemy lines to rob a bank.

Talisman and Shamrock, part of the Emmerian forces scrambled to defend Gracemeria, are assigned together due to neither pilot having a wingman, forming Garuda Team.

As the battle begins, Melissa witnesses Estovakian aircraft destroy the bridge that Matilda's school bus is supposed to be crossing.

Later, Melissa hears Matilda's voice in a radio broadcast from Estovakian-occupied Gracemeria and begins a journey back to the city to reunite with her.

It is revealed that Estovakia is planning to deploy chemical weapons on Gracemeria in a scorched earth defense, should Emmerian forces reach the city.

That evening, Garuda Team conducts an aerial patrol over Gracemeria, during which Shamrock learns his family was killed in the war and announces his intent to retire.

With assistance from Melissa, Matilda, and Voychek, the Emmerian military traces the attack to "Chandelier", an Estovakian anti-asteroid railgun repurposed to destroy Gracemeria.

[10] In part due to its Xbox 360 exclusivity, the game only sold 700,000 copies, the lowest of any mainline entry in the Ace Combat series.