Opera is the most complete form of theatrical representation, characterized by musical accompaniment, both instrumental and vocal. It has played an important role in sociocultural spheres, affecting the various social strata and reflecting customs and ideas in different centuries. Composers have created pieces that have also shown the development of medicine. Since the birth of opera in seventeenth century in Italy, neuroscience has played an important role in influencing the representation of madness and neurological aspects. From the Folly of the Renaissance, a path toward a representation of madness was developed, initially linked to the myths of classical antiquity. In the seventeenth and eighteenth centuries, madness was represented as comical or funny, of a loving nature and influenced by the spread of the Commedia dell'Arte (Comedy of Art). In the nineteenth century, with the rise of the first scientific theories of the mind, insanity took more precise connotations and was separated from other psychiatric and neurological diseases. The operas of the twentieth century depicted psychiatric and neurological diseases, taking into account newer medical and scientific discoveries.