Inside the human body, roughly 37.2 trillion cells work energetically 24 hours a day and 365 days a year. Fresh out of training, the cheerful and somewhat airheaded Sekkekkyuu AE3803 is ready to take on the ever-so-important task of transporting oxygen. As usual, Hakkekkyuu U-1146 is hard at work patrolling and eliminating foreign bacteria seeking to make the body their new lair. Elsewhere, little platelets are lining up for a new construction project. Dealing with wounds and allergies, getting lost on the way to the lungs, and bickering with similar cell types, the daily lives of cells are always hectic as they work together to keep the body healthy!

Due to poor lifestyle choices, a certain human's body is in constant turmoil. With germs, bacteria, and foreign substances abound, the jobs of various cells become increasingly difficult and dangerous. As some of the unfortunate ones who matured in this chaotic environment, Sekkekkyuu AA2153 and Hakkekkyuu U-1196 strive to fulfill their duties—even if it means seeing many of their fellow cells lose their lives in duty. Set in an environment vastly different from its parent story, Hataraku Saibou Black portrays the cells' struggles as they try to maintain the body's health. However, the human's condition continues to deteriorate, and whether or not these efforts will amount to something concrete depends on the cells!

In her first life, the renowned and genius surgeon Dr. Aoi Takamoto was Elise de Clorance, a villainess of noble descent. Elise's selfishness, insolence, and obsessive love for her fiancé—Prince Linden de Romanoff—led to the deaths of her family members and, eventually, herself. Only after being reborn did Elise realize the error of her ways and decide that, instead of ruining lives, she would devote herself to saving them. But a tragic airplane crash robs her of her dreams too soon. By a miracle, Elise wakes up in her original body before her official engagement to Linden. Recognizing the chance to cherish her loving family and free Linden from an unwanted marriage, Elise wishes to use her advanced medical knowledge to continue down the path of saving lives. In a deal with the emperor, Elise is given only six months to prove that her true place is not on the throne, but rather with the wounded and ailing who desperately need her help.

At first glance, Ramune may not seem like a professional doctor—he is crass, rude, and often acts halfheartedly. But his true brilliance shines through once his patients pay him a visit: he is able to diagnose and treat all sorts of strange, mysterious diseases that come his way. From a young student whose fingers have turned into chili peppers to a child whose tears are made of condiments, Ramune is able to tap into a kind of innate, otherworldly sensibility that enables him to decipher the roots of their source. But finding the proper cure for these illnesses comes at a valuable price, and money certainly cannot be used to pay it.