Some authors sustained that the pessimistic thought of the Italian writer and philosopher Giacomo Leopardi (1798–1837) may be attributed to his unhappy life, characterized by several health problems. His philosophical theories appear as the result of depressive and melancholic state, related to his precarious health conditions, so limiting their intrinsic values. Several authors formulated various hypotheses on the diseases that Leopardi suffered from and postulated different theories on the cause of his early death. This article assumed that Leopardi may have been affected by juvenile ankylosing spondylitis, conditioning spinal deformities, relapsing-remitting uveitis, urinary tract and bowel tract problems, and acute arthritis. Chest deformity, as a complication of juvenile ankylosing spondylitis, may have caused progressive cardiorespiratory failure, worsened by recurrent bronchial and pulmonary complications, until his death caused by acute right ventricular heart failure. The acknowledgment of a physical cause of Leopardi’s disease contributes to reevaluate his “cosmic pessimism” as an original expression of his thought, so leading a general revaluation of the figure of one of the most important European thinkers of the 19th century.