The giant honeycomb oyster Hyotissa hyotis occurs at a high density in the shallow subtidal rocky bottom of Jeju Island off the south coast of Korea, where the sea surface temperature ranges from 14°C to 25°C seasonally. Unlike other oysters, H. hyotis has an extraordinarily large adductor muscle (AM) that accounts for more than 40% of the total tissue weight. This study analyzed the proximate composition, amino acids, and fatty acids of the AM of H. hyotis in Jeju Island to evaluate the nutritional potential. For the analyses, oysters were grouped based on their reproductive condition as prespawning (May–August), spawning (September–November), and postspawning (December–April). The AM contained a high level of protein (54.7%–69.4%) followed by carbohydrate (16.0%–25.3%) and lipid (4.5%–9.9%) throughout the year, indicating that the AM is enriched with protein. The total amino acids (TAA) in the AM ranged from 9.4 to 12.9 g/100 g dry weight annually, and essential amino acids accounted for up to 36.7% of the TAA. Like other marine bivalves, the AM contained a high level of taurine, which accounted for 26.5%–28.5% of the total free amino acids. The AM also included high levels of essential fatty acids, such as palmitic acid, docosahexaenoic acid, and eicosapentaenoic acid, as these fatty acids accounted for 35.9%–37.0% of the total fatty acids. The AM of prespawning oysters collected during May and August contained comparatively higher total proteins and carbohydrates. Results suggested that, like scallops and pen shells, the AM of the giant honeycomb oyster is highly suitable as seafood, and H. hyotis should be considered as a species of high potential for future aquaculture efforts.