The sequel takes place in 20XX, some unknown time after the first game. The four goddesses are shown fighting Arfoire, who has activated her HDD powers. The goddesses are quickly defeated, and Nepgear surrenders. They are held captive in the new landmass known as the Industry Graveyard. IF and Compa arrive there as well, and find out that their friends are in trouble. They attempt to proceed, but a giant mech by the name of Judge blocks their path. In an attempt to stall for time, IF singlehandedly fights Judge while Compa frees Nepgear. They return to find IF damaged, and Nepgear tries to fight Judge. Unfortunately, the mech is too powerful for them, so Nepgear uses the last of her energy to temporarily blind Judge, while passing out in the process.

The gameplay for the sequel has been revised since the first game. Instead of dungeons consisting of one big map, each dungeon is split into sections, through which the main characters Nepgear, UNI, Ram, and Rom must travel through to proceed. The random encounter feature in the first game has been removed, instead replacing them with monsters who will appear in the dungeons and begin to chase the player on sight. Various actions can be carried out while in the dungeon. Small cubes can be picked up by pressing the X button while near them. When approached by an enemy, pressing Square will swing your weapon in front of you. When an enemy is encountered this way, Nepgear's party gains an upper hand through a Symbol Attack. Some crystals must be picked up while in a dungeon.

There are several different endings, which primarily depend on the amount of shares a landmass has (in the case of landmass specific endings), maxed Lily Rank for specific characters, and in special cases, if the player has recruited certain characters or witness certain events or not. If the player has not completed the criteria for an ending other than Normal, then the player will re