The razor clam Sinonovacula constricta is a eukaryotic benthic intertidal bivalve species that is tolerant to different heavy metals, such as cadmium ion (Cd2+). However, the mechanism by which S. constricta responds to Cd2+-induced stress remains unclear. In this study, eight transcriptome libraries were constructed and sequenced using razor clams exposed to Cd2+ for 12 and 48 h. A total of 18,330 unigenes with an average length of 500 bp were annotated. Among these 18,330 unigenes, 582 and 649 displayed differential expression profiles at 12 and 48 h in the gill, respectively. The corresponding differential unigenes in the hepatopancreas were 1056 and 382. Gene Ontology annotation revealed that these unigenes were highly pronounced in metabolic process, cellular process, binding, and catalytic activity. Notably, ROS production-related genes, such as heat shock proteins 32, metallothionein, and glutathione, were synchronously enriched in all experimental samples with induced expression profiles, which was also validated by qPCR. Our results highlighted the relation between immune regulation and Cd2+-induced stress in razor clam and provided new insights into the molecular mechanisms of heavy toxicology.