The book opens with a long satirical preface, Democritus Junior to the Reader, in which Burton explains his borrowed name. Hippocrates once found Democritus in his garden at Abdera among the carcasses of beasts he had cut up, searching for the seat of black bile so that he might cure melancholy in himself and teach others to prevent it. Burton takes up that unfinished work, surveys the follies of kingdoms, professions, and persons, and concludes that all the world is melancholy or mad. His own motive is frank: he writes of melancholy by being busy, to avoid melancholy, for idleness is its greatest cause and business its best cure.
The First Partition defines the disease and traces its causes. Melancholy in disposition, the passing heaviness that follows any sorrow, need, or care, spares no one; neglected, it settles into a habit, a chronic dotage without fever whose ordinary companions are fear and sadness without apparent cause. Burton sorts the settled disease by seat into head melancholy, melancholy of the whole body, and melancholy of the hypochondries, then catalogues causes from God, devils, witches, and stars down through old age, inheritance, diet, bad air, immoderate exercise, idleness, solitariness, and the passions, with overmuch study earning a digression on the misery of scholars.
The symptoms follow: causeless fear and sorrow, suspicion and jealousy, sudden swings between laughter and weeping, fixed delusions, and a restless mind that builds castles in the air and cannot let a grievance go, returning to it a thousand times against its will. The pain, Burton insists, exceeds bodily torture; if there is a hell upon earth, it is found in the melancholy man's heart, and the prognostics warn that the disease may end in despair or self-destruction. That severity is his argument for taking sadness seriously and treating it early.
The Second Partition turns to cures. Unlawful means are dismissed, and lawful ones begin with prayer and proceed through physic. The heart of the cure is the rectifying of the six non-natural things: diet, retention and evacuation, air (the excuse for a famous digression that roves over the whole globe like a hawk let off the fist), exercise of body and mind, sleep, and the perturbations of the mind. The patient must be willing and must resist beginnings, and above all must not smother grief, for grief concealed strangles the soul while a friend's counsel is a charm. Music, mirth, and merry company are medicines in their own right; a long consolatory digression offers remedies against poverty, imprisonment, banishment, the death of friends, slander, and every ordinary discontent; drugs and surgery come last and with caution.
The Third Partition treats the two grand special forms. Love-melancholy is anatomized through its causes, idleness again chief among them, its absurd symptoms, and its cures, of which the last and best is to let lovers have their desire and marry; jealousy follows as its bitter appendix. Religious melancholy, a species Burton claims as his own, is love-melancholy whose object is God: in excess it breeds superstition, enthusiasm, and self-appointed prophets, in defect atheism and despair, which he answers with physic, good counsel, and comfort. The whole work then closes on one short precept: be not solitary, be not idle.