The quality aspects of Ostrea edulis (O. edulis) cultured in Valli di Comacchio were examined across different seasons. Nutritional quality parameters, antioxidant activity, total carotenoids, and contaminants were determined in winter, summer, and autumn (December, June, and October). Seasonal variations in nutritional parameters were observed. In particular, in the winter samples, proteins, eicosapentaenoic acid, docosahexaenoic acid, threonine, tyrosine, valine and methionine, isoleucine, potassium, and carotenoids showed the highest values, whereas oleic acid, linolenic acid, lysine, and magnesium exhibited the maximum values in the summer. Finally, lipids, carbohydrates, histidine, and magnesium were present at high values in the autumn. The antioxidant activity values differed between the two methods used (DPPH and photochemiluminescence assays); however, the oysters collected in June presented lower antioxidant capacity. Contaminant levels were always below the imposed concentration limits; however, higher levels of toxic metals were detected in the winter, while polycyclic aromatic hydrocarbons were detected in the summer and autumn. It is important to monitor the nutritional and toxicological quality of Ostrea edulis throughout the cultivation seasons, not only to enhance knowledge of this species and improve its cultivation systems but also to determine the optimal period for human consumption from both nutritional and toxicological perspectives.