Similar to the Kingdom Hearts franchise, Kamikaze Hobo Symphony takes place on a three-dimensional, largely open plane where the player is able to roam freely, a map made readily available for navigation with marks for various quests. Combat is hack-and-slash, with various abilities such as the super moves "Ballads" available through a HUD menu that can be accessed at any time. For each hit that the player lands, they gain more experience points, and the amount of experience points they gain double for each hit in a combo, a combo being seven or more consecutive hits. When the player reaches their maximum experience points, they level up and gain access to new abilities and become stronger overall. Rhythm and music are prominent in combat, combos usually having to be timed with music. Smaller enemies usually come in hordes or waves, the final wave typically followed by a battle with one or more giant enemies, in which acrobatics are needed to be used.
In a grim pseudo-cyberpunk future, giant creatures known collectively as "The System" destroy and terrorize countless parts of the world. The System have a hivemind and, in spite of their size, attack with master strategy and untold damage. Along with The System came millions of half-organic drones they seem to birth, known as "The Security", who attack in enormous swarms and are far smaller. Mankind's only hope rests in those who had undergone a mysterious process called "conversion" when The System and The Security had first made impact many years ago. Conversion was carried out by The Security, who had chosen a select few for reasons unknown to try and penetrate with their half-cybernetic technology and infect with some sort of agent that would theoretically turn the people into one of them. The process of conversion, however, was somehow cut short, all The Security who had began the process forced to retreat before it could be completed. These people, though at first badly wounded, discovered they now possessed a mighty power; they could summon magical musical instruments from their body at will to perform devastating attacks that had the potential to take down hordes of Security, even those of The System if executed correctly. These few were known to some as "The Band". However, when the United Nations made the decision to gather them all together to play a celestial ballad known as "The Symphony" as a team to possibly overwhelm The System's forces in a time of dire need, most of them vanished, choosing to live lives of peaceful anonymity and not have to be troubled with a war that they did not choose and was not theirs to fight.
Years later, the threat of The System is stronger than ever, and the human forces are being exhausted. A middle-aged homeless man on the streets of a broken New York by the name of Keith holds the key to mankind's survival in the form of his Instrument known as "The Millenium Pick". When Keith's estranged wife and daughter are caught in an attack by The System, he must summon his Instrument and call together the other members of The Band in hopes of saving his family and the world.