Mushishi is set in an imaginary time between the Edo and Meiji periods, featuring some 19th-century technology but with Japan still as a "closed country". The story features ubiquitous creatures called Mushi (蟲?) that often display what appear as supernatural powers. It is implied that there are many more lifeforms more primitive than "normal" living things such as animals, plants, fungi and bacteria, and Mushi is the most primitive of all. Due to their ethereal nature most humans are incapable of perceiving Mushi and are oblivious to their existence, but there are a few who possess the ability to see and interact with Mushi. One such person is Ginko (ギンコ?), the main character of the series. He employs himself as a Mushi Master (蟲師 mushi-shi?), traveling from place to place to research Mushi and aid people suffering from problems caused by them.
The series is an episodic anthology in which the only common elements among episodes are Ginko and the various types of Mushi. There is no overarching plotline. The most frequently seen character is an otherworldly-looking man named Ginko, who is voiced by Yuto Nakano in the original version and by Travis Willingham in the English dub. Ginko is a rare person who attracts mushi, which inspires a lifestyle of constant wandering. He also smokes in order to keep the mushi away. In terms of personality, Ginko is generally laid back and focused on his work. However, he can be very serious when it comes to protecting people from mushi. He also often stresses that the mushi are not evil, but merely trying to survive like everyone else. A majority of the stories do not focus on Ginko, but rely on him as a catalyst to move the story forward by diagnosing or curing mushi-related illnesses and phenomena.