The Manila clams Ruditapes philippinarum are worldwide shellfish in marine intertidal zone, which usually encounter a great risk of salinity stress in their coastal habitats. The integrated analysis of transcriptomics and metabolomics were performed to investigate the transcriptional and metabolic profiles of the clams in response to abrupt salinity decrease. The comparative transcriptomics uncover the changes of genes involved in ion channel activation, neuronal activity, energy metabolism at salinity-stressed condition. The metabolomics analysis reveals that glucose-succinate pathway may play a critical role for energy metabolism during the osmotic stress. The multi-omics analysis reveals that neural adaption to salinity stress may be regulated by arachidonic acid and glutathione metabolism. The important metabolites may be served as the signaling molecules in response to acute salinity stress. These findings provide great insights on the molecular and metabolic strategies of clams in response to salinity stress in marine ecosystems