E3 ubiquitin ligase (E3s) plays an important role in ubiquitin proteasome pathway, proteins containing homologous E6-AP carboxyl terminus (HECT) domains. However, the role of HECT E3 ubiquitin ligase in mollusk was rarely explored. In this study, we performed a genome-wide analysis of the HECT domain-containing gene in Ruditapes philippinarum to identify and predict the structural and functional characterization of HECT genes in response to abiotic and biotic stress. A total of sixteen members of HECT gene family were identified and analyzed for the gene structure, phylogenetic relation, three-dimensional structure, protein interaction network, and expression patterns. Experimental results demonstrated that Rph.HUWE1, Rph.HECTD1, Rph.Ubr5 were significantly up-regulated in response to heat stress and bacterial challenge. Taken together, our data provide insights into the potential function of HECT E3 ligase in heat stress and Vibrio anguillarum infection.