The entire countryside comes to a halt midday to witness a rare solar eclipse that is rumored to allow the average person to see Mushi. Unable to avert their gaze, the air is full of awe and wonder—but those who know the Mushi are preparing for the eclipse's aftermath. Based on a prediction from Tanyuu Karibusa, the cursed recorder, Mushishi Ginko finds himself in a very unlucky farming village. Immediately following the solar eclipse, a strange black cloud begins to gather in the sky and blocks the sun once more. Suspecting it to be the work of a Mushi known as Hihami, Ginko seeks to liberate the village from perpetual darkness. However, it seems that not all of the villagers are eager to return to the light.

Mysterious, unknowable creatures alien to the laws of nature—known only to some and feared by others—Mushi lie behind many of life's strange phenomena. Long ago, a Mushi of terrifying power threatened to extinguish all life. The Minai clan of Mushishi were born from those who stopped this malevolent force, their members bound by duty to serve as retainers to the Karibusa family, within whom the Mushi remains sealed. The Mushishi Ginko is given a job request from Tanyuu Karibusa: oversee the work of the head of the Minai clan, Kumado Minai, in investigating an abandoned village where dead wood and even houses spring back to life as flourishing plants. Though the Minai clan are oddly ruthless among Mushishi, even more peculiar is their widespread dull character, with little appreciation for beauty or sentiment. Tanyuu believes there is more to this trend than meets the eye. Ginko aims to answer her curiosity as he follows Kumado into a Path of Thorns, a place where Mushi flow from their own strange sources into the world of the living. Rare and deadly varieties of Mushi lurk in these depths, along with the secret nature of the Minai clan's resolve to their ancient task.

Mushi: the most basic forms of life in the world. They exist without any goals or purposes aside from simply being. They are beyond the shackles of the words good and evil. Mushi can exist in countless forms and are capable of mimicking things from the natural world such as plants, diseases, and even phenomena like rainbows. This is, however, just a vague definition of these entities that inhabit the vibrant world of Mushishi, as to even call them a form of life would be an oversimplification. Detailed information on Mushi is scarce because the majority of humans are unaware of their existence. So what are Mushi and why do they exist? This is the question that a Mushishi, Ginko, ponders constantly. Mushishi are those who research Mushi in hopes of understanding their place in the world's hierarchy of life. Ginko chases rumors of occurrences that could be tied to Mushi, all for the sake of finding an answer. It could, after all, lead to the meaning of life itself.

Ghostly, primordial beings known as Mushi continue to cause mysterious changes in the lives of humans. The travelling Mushishi, Ginko, persists in trying to set right the strange and unsettling situations he encounters. Time loops, living shadows, and telepathy are among the overt effects of interference from Mushi, but more subtle symptoms that take years to be noticed also rouse Ginko's concern as he passes from village to village. Through circumstance, Ginko has become an arbiter, determining which Mushi are blessings and which are curses. But the lines that he seeks to draw are subjective. Some of his patients would rather exercise their new powers until they are utterly consumed by them; others desperately strive to rid themselves of afflictions which are in fact protecting their lives from devastation. Those who cross paths with Mushi must learn to accept seemingly impossible consequences for their actions, and heal wounds they did not know they had. Otherwise, they risk meeting with fates beyond their comprehension.