The player returns as the role of the pilot of the Vic Viper spaceship to battle the second onslaughts of the Bacterion Empire, under the new leadership of Gofer, the giant head. Gradius II has kept the gameplay from the original game, but infused it with enhancements brought from the spin-off, Salamander (Life Force). This is primarily evident in two of the weapons configurations that are selectable. Another first in the series was the inclusion of the "boss rush" (also known as "boss parade" or "boss alley"), a level designed entirely with only boss confrontations.

Gradius II retains the selection bar from Gradius, but now the player can choose between four different weapon configurations and progressions. All schemes have speed-up and multiples (Options), but have differing 'Missile', 'Double' (laser), and 'Laser' weapons. The player can have at most four multiples. Additionally, there are also two types of shielding to choose from: shield and forcefield. The shield option adds more durability, but only for the front of the Vic Viper, while the forcefield adds protection for the entire spacecraft, albeit only against three hits.