Rune Factory 4 begins with the male or female protagonist on an airship, sent to deliver something important to a town known as Selphia. However, the trip goes wrong when a couple of men attack the protagonist to obtain the important delivery item. A battle ensues and in the midst of it all, the protagonist falls off of the ship and loses their memory in the process. Upon waking up, they realize that they have been named prince/princess of Selphia and must now take on the responsibilities of royalty, all the while working as the common citizens of the town do.

The gameplay follows the standard set up by previous games in the Rune Factory series, featuring farm simulation similar to that in the Harvest Moon series and battles typical of a role-playing game. New features include being able to play as a female from the start and progressing long-term relationships with eligible characters before proposing. The game's story is split into three parts, with the main plot encompassing the first two parts while a bonus story is included as the third.