Metamorphosis is a common developmental strategy within the animal kingdom. In marine invertebrates, this is characterized by a habitat shift from the pelagic into the benthos, accompanied by dramatic morphological, physiological, behavioral, and ecological changes in the metamorphosing larvae. Studies on some commercially cultured molluscan species have demonstrated the significant role played by neuronal and neuroendocrine signaling in the regulation of this process. However, it is still unclear how external and internal messages translate into the complex morphogenetic processes observed during this key developmental transition. In this study, we identified molecular targets crucial in the metamorphosis of the giant clam, Hippopus hippopus, an economically important but vulnerable species, by using comparative transcriptomics and pharmacological assays. We identified neuroendocrine-related genes expressed in the non-competent larvae, competent larvae, and metamorphosed juveniles, and described their gene expression patterns over the course of metamorphosis. Our results also revealed the potential role of neuroactive chemicals, such as GABA, serotonin, epinephrine, and L-DOPA, in H. hippopus metamorphosis. In particular, epinephrine effectively induced settlement and triggered faster metamorphosis in the giant clam. Findings from this study will aid in the development of protocols for effective settlement induction in cultured giant clams and contribute to a more comprehensive understanding of the molecular pathways governing molluscan metamorphosis.