The game boasts a roster of playable original ships, such as the balanced Amada Vipros, the fast Phyxius, the damage-dealing Zaiva, and the finesse Xelcor. It also features a varied array of guest fighters, serving as cameos from other SHMUP games, both well known and obscure. There is even a certain dual-type Electric/Flying Legendary Pokémon that appears as a guest fighter.

The plot of Xeno Fighters R involves BRES, a group of humans subverted and corrupted by a race of hostile extraterrestrials known as the Keto, launching attacks against the forces of ATHENA through various periods in Earth's war history. The guest fighters and the EX Stages do not have any connection to the plot. Repel the extraterrestrials and save the planet once again!