Chō Jikū Yōsai Macross: Skull Leader is based on the anime series Macross, narrating its initial chapters and focusing on one of its primary characters, Hikaru Ichijyo. Like Remember Me, it is a turn-based strategy game; however, it cannot be considered a sequel, since it does not continue the story and has many gameplay-related differences. The battles take place on an isometric screen. Instead of deploying individual space ships and mechs, as it was the case in Remember Me, the player positions human commanders, each controlling several of the aforementioned craft. The player can change formations in order to gain advantage in battle. Commanders are navigated on the screen in turn-based fashion. When an enemy is in range, the player has to choose an attack technique to employ against him. The ensuing battle is then displayed on a separate screen, proceeding automatically.

The year is 2009, and humanity's most powerful weapon is the Super Dimension Fortress One, also known as "Macross", an alien starship containing powerful technology. On a fateful day, a fleet of an alien warrior race known as Zentradi was hit by Macross' automatic defense system, inadvertently starting Space War I.