We previously investigated the molecular mechanisms associated with resilience to ocean acidification in Crassostrea virginica. There were significant differences in SNP and gene expression profiles among oysters reared under normal and OA conditions. Both of these approaches showed similar results, particularly in genes related to biomineralization, including perlucin. In this study, we used RNAi or gene silencing to validate findings and confirm the protective role of perlucin associated with resilience to OA. Silenced oysters under acidification stress were the smallest, had shell abnormalities, and had significantly reduced shell mineralization, thereby indicating that perlucin does help larvae mitigate the effect of OA.