Blue Gender takes place in the not too distant future in a world where things have gone terribly wrong for humanity. Humans have been replaced at the top of the food chain by the Blue, a race of bug-like aliens that have colonized Earth and pushed humans aside. A space station, Second Earth, has been constructed as a safe haven for humans, with the hope of one day reclaiming the Earth once more. Yuji Kaido was cryogenically frozen, having been suffering from a disease known as B-Cells. Once awakened, he joins a team of soldiers that have come to Earth to extract him. Unfortunately, nothing goes according to plan as they make their way back to Second Earth. Yuji will have to deal with the horrors of fighting a bloody war as he and the fighters from Second Earth look to survive. Will they be able to win back Earth without losing their humanity?

As fifteen children at a summer camp enjoy their carefree vacation together, they stumble upon a small cave near the beach. The group finds a mysterious room deep within its caverns, where they meet a strange man who calls himself Kokopelli. The man invites the children to play a game that involves taking turns controlling a robot to protect the Earth against aliens. Thinking it might be an interesting computer game, all but one of the children sign a contract agreeing to play. Later that day, the giant robot appears in person and the children are teleported into its cockpit, where they find Kokopelli, who pilots a fight against a similar robotic creature that has appeared nearby. After winning the battle, Kokopelli tries to apologize but is interrupted as the children are teleported back to the ground in the midst of the carnage. As the bewilderment following the fight settles, the robot suddenly disappears and the children are left scared and confused. Despite seeming like a harmless game at first, the children never anticipated the stakes of this game and how their pasts would intertwine with their decisions going forward.

The world is in the midst of the industrial revolution when horrific creatures emerge from a mysterious virus, ripping through the flesh of humans to sate their never-ending appetite. The only way to kill these beings, known as "Kabane," is by destroying their steel-coated hearts. However, if bitten by one of these monsters, the victim is doomed to a fate worse than death, as the fallen rise once more to join the ranks of their fellow undead. Only the most fortified of civilizations have survived this turmoil, as is the case with the island of Hinomoto, where mankind has created a massive wall to protect themselves from the endless hordes of Kabane. The only way into these giant fortresses is via heavily-armored trains, which are serviced and built by young men such as Ikoma. Having created a deadly weapon that he believes will easily pierce through the hearts of Kabane, Ikoma eagerly awaits the day when he will be able to fight using his new invention. Little does he know, however, that his chance will come much sooner than he expected...

Half a year has passed. Arriving in the Iron Fortress, Ikoma and Mumei set foot in Unato: another ravaged zone that fell into the grip of the deadly Kabane. In this war-torn zone, the group fends off more dangerous Kabane that are attacking with patterns they had never seen before. The Iron Fortress crew eventually meet up with a survival group which requests their aid in reclaiming the zone. The newly forged alliance ventures deeper into the area of the castle and investigates the peculiar case of these new Kabane. But their search for answers unearths truths that are far more horrifying than they imagined. Forced to confront the reality behind the Kabane, Ikoma, Mumei, and their allies come to realize the despair buried within Unato.