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?

In the wake of an earthquake that devastated most of the city, Tokyo has been rebuilt in record time due to the development of humanoid robots known as boomers. After the disaster, these machines now service the city as cheap labor. Genom Corporation is the mastermind behind the boomers, having become so rich and powerful that they have extended its influence into space. However, all is not well with the boomers. Random breakdowns in their neural structure are causing some of them to go berserk, destroying property and killing humans in violent rampages. To combat this, Tokyo has formed the Advanced Police, a peacekeeping force with jurisdiction over boomer matters. There are also rumors of a second group known as the Knight Sabers, a vigilante unit operating from the shadows. Trying to investigate the Knight Sabers, the adventurous Linna Yamazaki travels to Tokyo in pursuit of her heroes. There, she finds the enigmatic singer Priscilla Asagiri, the beautiful entrepreneur Sylia Stingray, and the exuberant Nene Romanova, each with their own reasons for coming together. As the struggle intensifies, the girls learn that the boomer problem might delve deeper than any of them could ever imagine.