The Mediterranean basin typically shows the ubiquitous presence of historical towns constituting a rich architectural heritage that has only recently become the object of conservation policy. Diagnostic knowledge can effectively contribute to the adoption of suitable conservation strategies. This work focuses on the historical building materials employed in the Sicilian town of Syracuse (Southern Italy), with the aim of identifying the causes and mechanisms of deterioration of the materials employed, as well as possible remedies. An extensive survey of the stones and their main decay morphologies within buildings was carried out. Laboratory analyses by optical microscopy, mercury intrusion porosimetry and ion chromatography were also performed. Several soft and porous calcarenites, having different mineralogical–petrographical and porosity features, were recognized. The study identified a decay scenario typical of a Mediterranean context, with sea spray as the main cause of decay, together with water and wind. Different decay levels observed in the stones were related to their fabric and porosimetric structure, but specific use and position within buildings also proved important. The findings of this study are of interest for similar urban and geographical contexts where soft and porous calcarenites are employed, and provide information for conservation works.