The ark shell Scapharca subcrenata is an important economic aquaculture species in China and Korea. In the latest years, mass mortality of S. subcrenata caused by outbreaks of vibriosis in summer has occurred frequently and leads to catastrophic economic losses. Nevertheless, the innate immune defense mechanisms of S. subcrenata are poorly understood at present. In this study, we aimed to explore the transcriptomic responses of S. subcrenata to Vibrio parahaemolyticus challenge and identify the candidate genes associated with maternal immune transfer and trans-generational immune priming. These findings would be beneficial for understanding the innate immune defense mechanisms in S. subcrenata.