Mercury contents were determined in surface sediments from the Central and Southern Adriatic Sea to gain insight into the processes, factors, and variables affecting its distribution. Mercury concentration was measured by thermal decomposition amalgamation atomic absorption spectrometry in samples collected by box-corer from Ancona to Santa Maria di Leuca during the CNR-PERTRE cruise (16/9-4/10/2016). Sediments were also evaluated for chemical-physical parameters (pH, Eh), biogeochemical composition (total carbon, inorganic carbon, total organic carbon, organic matter) and grain size. The average mercury concentration in the Adriatic Sea sediment was 0.053 mg/Kg (d.w.), range 0.011–0.12 mg/Kg (d.w.). Mercury content was mainly affected by grain size and organic matter (OM) distribution, whereas anthropic factors exerted a limited influence. Concentrations followed the distribution of sediment types (clay > silt > sand) due to Adriatic Sea hydrodynamics and were well below the regulatory limits in all samples.