The Tonnara of Favignana, officially called “Ex Stabilimento Florio delle tonnare di Favignana e Formica”, is an ancient tuna fishery, with an annexed facility for the conservation of the catch, located in Favignana in the Egadi Islands. With its 32,000 square meters, of which 3/4 are covered, it is one of the largest tuna fisheries in the Mediterranean. This work investigates the geotechnical dynamic characteristics of the foundation soil of the Tonnara of Favignana through a comprehensive program of in situ investigations and laboratory tests. The purpose of this paper is to synthesize all available information into a representative geotechnical model of the site where the historical building is situated. Through a detailed analysis of the collected data, it was possible to assess the ground response analysis at the surface in terms of acceleration time history and response spectra. The outcomes of the ground response analysis provide a valuable contribution to the safeguard of historical buildings from the seismic risk and to the development of effective seismic improvement interventions.