Alien Syndrome is based on the arcade version of Alien Syndrome. However, some distinct changes have been made. The level layouts have been changed and the game now features a flip screen instead of scrolling, which causes the enemies to always appear in the same location when entering a new location. The game is also now littered with hazardous tiles on the ground that will kill the player if they step on them and these tiles will fire the occasional shot that needs to be avoided. The tiles can only be temporarily disabled by shooting them. Unlike the arcade version, the first player is always Ricky and the second player is always Mary, and they take turns playing instead of being able to play co-op.
Gameplay involves controlling one of two alien characters, either Ricky or Mary , as they navigate through levels filled with deadly enemies and hazardous terrain. The gameplay is fast-paced and action-packed, requiring players to shoot enemies and avoid hazards while also managing the enemy fire that can be triggered by stepping on certain tiles.