Mussel Mytilus coruscus is a coastal economic culture species. However, massive mortalities associated with low-salt environments caused by persistent rainfall and freshwater inflow threaten its development. Herein, we examined its survival under different low-salt conditions. The survival rate of umbo and eyed larvae significantly decreased with the decline in salinity or prolonged stress time. The umbo larvae were more tolerant to low-salt stress than the eyed larvae. When the salinity levels dropped suddenly, the adults could not survive below 16‰ salinity, and their survival rate decreased faster with the increase in salinity span or the decrease in final stress salinity. However, the adults could tolerate a lower salinity levels when it dropped slowly, and their low-salt tolerance limit was 10‰. Therefore, mussel M. coruscus could adapt to a lower salinity only when the salinity levels dropped gradually. We also explored the physiological and adaptive responses of the foot in response to chronic prolonged low-salt stress by transcriptome analysis. We found that most genes in the “calcium ion binding” term and the osmoregulation-related genes were significantly induced in the salt 12 and 14 groups, suggesting the strong positive response in calcium signal transduction and osmoregulation under prolonged low-salt stress. The HSP70 and IAP genes were upregulated, suggesting that mussel M. coruscus protects itself from low-salt environments by inhibiting apoptosis. The cytoskeleton and cell cycle were inhibited, and the byssus attachment-related genes, such as tyrosinase and foot-protein genes, were suppressed, suggesting a negative response of cell division and byssus thread attachment during prolonged low-salt stress. The enhancement of carbohydrate metabolism indicated its positive role in maintaining energy homeostasis during prolonged low-salt stress. Our findings contribute to the improvement of culture technology and the guidance of selective breeding program for mussel M. coruscus and enhance our understanding of low-salt adaptation mechanism.