Alien Syndrome is played as a top-down shooter, with players turning their characters the direction they would like to shoot. The game has 40 levels,[4] with 5 bosses and 15 mini-bosses. Players customize their character to expand in-game strategy options.
Alien Syndrome has 80 different weapons to use and hundreds of armor types as well as bonus items. Players are accompanied by a robotic drone (SCARAB) that serves as a storage space for items as well as a backup for the main character. As a constant companion, SCARAB can assist in fights and grant on-demand access to the character's cache of weapons and armors. Players have both a life meter and a constantly refilling energy meter, with the latter reflecting shield power.
The game also features co-op multiplayer for up to 4 people on one screen for the Wii version. On the PSP version, the game features co-op multiplayer via a WiFi connection.