Millennia later, in the time when the game is set, a Skaven rocket disguised as a twin-tailed comet disrupts the Great Vortex. It drained Chaos energy at the expense of locking Caledor and his mages in time, eternally casting spells to maintain the vortex. This manifested itself as the Great Vortex, accomplished with the help of the Lizardmen leaders, the Slann. Aenarion 'the Defender' mustered armies whilst Caledor Dragontamer planned to drain magical energy from the world, thus stopping the Chaos invasion. Two High Elf heroes in Ulthuan responded to this threat. The stellar gates which the Old Ones used to enter the world collapsed, leading to a flood of Chaos that was held at bay by the Lizardmen. The Old Ones, powerful godlike beings, created races in the Warhammer world to fight the forces of Chaos. The campaign can also be played online with another player in co-operative or head-to-head modes. Mortal Empires must be downloaded manually from Steam, but is free for players who own both games. In addition, players who own both Total War: Warhammer and Total War: Warhammer II have access to a huge combined campaign called Mortal Empires, which is more of a sandbox experience.

It is a narrative-focused campaign where each of the playable races has its own story and cutscenes. The main campaign of the game is called Eye of the Vortex. The Tomb Kings and Vampire Coast (a faction of undead pirates) debuted later as paid downloadable content factions, along with The Huntsmarshal's Expedition, the Chevaliers de Lyonesse (a knightly order), and the Sisters of Twilight (a faction of Wood Elves).

The game's announced races in the campaign include the Lizardmen, High Elves, Dark Elves and Skaven. Those who own races from the first game will have the same races unlocked for multiplayer in the second game. The game also has a custom battles mode where players can create customised real-time battles, as well as online multiplayer battles. When armies meet, they battle in real-time. Players engage in diplomacy with, and fight against, AI-controlled factions. In the campaign, players move armies around the map and manage settlements in a turn-based manner. Total War: Warhammer II features turn-based strategy and real-time tactics gameplay similar to other games in the Total War series.

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