VenomSpider-Man: Separation Anxiety is an engaging side-scrolling beat'em up game that immerses players in a narrative drawn from Spider-Man comics. Players can choose to control either Spider-Man or Venom, embarking on a mission to thwart the Life Foundation's nefarious plans. The game builds on a storyline inspired by a mini-series where the Life Foundation has extracted five symbiotes from Venom, aiming to bond them with soldiers to form a formidable army. Players must navigate various environments, including streets, woods, and underground complexes, while battling enemies and bosses.

Gameplay involves a range of combat moves such as punching, kicking, and executing combos. Players can also collect superhero icons throughout the game, which summon assistance from iconic allies like Daredevil, Ghost Rider, Hawkeye, and Captain America. This feature adds a strategic element to the gameplay, enhancing the overall experience and providing a nostalgic connection to the broader Marvel universe.