Isaac Clarke is the main character and protagonist in Dead Space 3. He is a systems engineer working for the Concordance Extraction Corporation. Prior to the Second Aegis VII incident, he was part of an emergency response unit of the USG Kellion, sent to the USG Ishimura to investigate and handle the ship's problems. Apparently the sole survivor of the incident, Isaac became stranded in space for a long period of time before he was rescued by an Earth Government ship. Three years after those events, Isaac was held in an asylum on Titan Station and was diagnosed with mental disorders, the most prominent being dementia that result in haunting illusions that taunt him throughout the game. In Dead Space 3, he still has the blueprint to destroy and create Markers. However, in the Awakening DLC, he witnesses the effects of dementia once again when he is exposed to one of the Brethren Moons.

After destroying the Site 12 Marker, Isaac escaped with resident Ellie Langford. Within the three years after the incident, they developed a romantic relationship but separated due to Isaac's refusal to help Ellie in combating the Markers. Ellie left to pursue a solution to the Marker crisis while Isaac remained on the New Horizons Lunar Colony, only to be called back by Cpt. Norton and Sgt. Carver who retrieve him to rescue Ellie. Isaac then is brought to Tau Volantis to rescue Ellie and discover the true meaning behind the Markers.