Shellfish culture, based on ecological and market assessment, is considered a driving force for socio-economic change in ecologically complex coastal systems such as lagoons throughout the Mediterranean area. To diversify fish production, the Pacific oyster Crassostrea gigas was cultured at commercial farms in the Varano Lagoon (SE Italy). The aims of this study were to evaluate through four condition indices (CI, CICG, CIE and AFNOR index), the Polydora index (PI), lipid content, quality and market aspects of oysters reared at two different sites (FO and LA) of the Varano Lagoon, which are characterized by different hydrodynamic conditions. The results of this study highlighted the potential economic benefits associated with sustainable aquaculture development in the Varano Lagoon, proving that the area surrounding the LA site was more suitable for oyster culture, reaching commercial size (60 mm) in a shorter time (6–8 months). Higher growth performance of oysters was observed in the spring, when the nutrient availability positively affected the feeding response of suspension feeders. The opposite was found in winter and in summer, when the decrease in growth could be due to the reduction of nutrient and to the increase of salinity, TSM and ISM. The presence of the mud blister worm (Polydora sp.) during rearing could be a real problem, as it damages oyster market value and threatens serious financial loss to the local farmers.