Long, long ago, the world was bound together on one great continent, but through years of war and strife, the world broke apart into countless smaller lands. The world has since continued as such, its inhabitants having nearly forgotten that their world was once whole. One day, three children from a land known as Kusukusu summon two young heroes from faraway lands: Lost Ninebell, a skilled swordsman who has lost his memory; and Millet Tearbell, one of the Three Sages of Greybell, and the daughter of the high priest. Now bound by the summoning contract, these two must work together to help their benefactors and return home.

Summon Night Granthese is a 3D action-RPG spinoff of the popular Summon Night series. Much like the previous title Summon Night Ex-thèse, the player controls two protagonists and can freely switch between them at any time. Lost is a skilled swordsman and is skilled in close combat, while Millet wields pistols and can attack from a distance. Unlike the previous title, both characters share status and attributes, though they have separate sets of equipment. Defeating monsters earns experience; combo chain attacks, which can include both characters on the fly, will earn bonus experience. When the player levels up, points can be distributed to increase the characters' attributes, but the effects are applied to both Lost and Millet.

The game largely takes place in a 3D world similar to modern Zelda games. However, towns are simplified to a menu which allows for shopping and speaking to other characters; it is often necessary to speak with NPCs multiple times to learn where to proceed in the story. The story itself is divided into chapters; exposition is presented as visual novel-style character stills with voiced dialogue. There are also occasional animated cutscenes. The story changes slightly depending on which character the player has chosen as their main protagonist.

In addition, there are also several major sub-systems in the game. Most important is the item crafting system, where the player can synthesize special items in various combinations to create other, more useful items such as potions and equipment. Results of different combinations are recorded, and it is also possible to learn recipes from other characters throughout the game. In addition, there is also the Summon system, which allows the player to choose from different creatures to change the properties of their special attacks. Different Summons can be assigned to Lost and Millet, and certain ones will even have different effects depending on who they are assigned to.