Iron Helix is a futuristic Sega CD game set during a cold war between humans and an alien race named Thanatosians. An Earth fleet, practicing target drills on a deserted planet, results in the crew of the destroyer, Jeremiah O'Brien, being infected by a mysterious virus altering their DNA. The alteration causes the ship's defense robot to perceive them as intruders and subsequently kills them. Amid the chaos, a technical glitch causes the O'Brien's computer system to mistakenly select Calliope, a peaceful Thanatosian planet, for annihilation using its potent weapon, "Iron Helix". The unfolding circumstances prompt the player, aboard the research vessel Indiana, to prevent this disaster. Due to the viral predicament onboard O'Brien, the player remotely operates a zoological robot, tasked with collecting uncorrupted crew DNA samples to unlock various sections and interact with the ship's systems.
Set far in the future, the human race is in the middle of a cold war with an alien race called the Thanatosians. During a target practice by an Earth fleet that will destroy an uninhabited planet, the heavy destroyer Jeremiah O'Brien is infected with an unknown virus that mutates the crew. No longer recognized due to the changes in their DNA, the O'Brien's security robot, simply known as "the Ship's Defender", assumes they are invaders and kills them. An apparent technical malfunction has caused the O'Brien's computer to believe that it was in a real life war situation, and select the planet Calliope as a target for destruction. Like all of the human fleet's Cerberus-class destroyers, the O'Brien carries a weapon known as "Iron Helix", which is capable of destroying all life on a planet in a single act. An attack on Calliope, a peaceful Thanatosian planet, would cause the war to go "hot".
The player is on board the scientific exploration ship Indiana, and is contacted by the Earth's forces in an attempt to stop the O'Brien, as it was the only ship nearby. As the ship is infected with the unknown virus, the player instead remotely controls a zoological robot that is sent over to explore. As much of the ship's systems are locked out using DNA detectors, the robot must collect uncontaminated samples of the crew's DNA to access different secured areas on board. The robot can also interface with dataports on the O'Brien to operate its systems, from opening doors to issuing executive commands.