In 1815–16, the small town of Noja (now called Noicattaro), on the Adriatic coast of southern Italy, was affected by a plague epidemic, the last manifestation of this disease in Italy and one of the last in Continental Europe. Besides having serious demographic consequences at local level, the plague also had a considerable influence on medical and scientific debate concerning the nature of the disease and its feasible cures. In the first part, this study reviews some of the most significant doctrinal positions on the subject emerging within the southern medical profession. In the second part, it concentrates on the therapeutic strategies actually experimented with in Noja, highlighting the rejection of traditional pharmacopoeia and mainstream treatments such as emetics, purgatives, and bloodletting. Yet the medicines validated and tested as an alternative to these therapeutic modalities were at best palliatives, if not at times highly toxic substances. As a whole, the analysis shows how, when confronted with the plague, medical science continued to grope in the dark, despite wanting to free itself from traditional dogmas; the doctors' intervention on the epidemic certainly had negative effects on the course of the disease and on the trend of the fatality rate.