In the present research, the effects of density (60 and 120 individuals /m²) and salinity (20 and 30) are examined on osmotic regulation and antioxidant responses of Sinonovacula constricta. The experiment lasted 72 hours. The concentration of Na⁺ and K⁺ in the hemolymph, the activity of SOD and MDA in liver, the activity of Na⁺/K⁺ -ATPase, and the expression of Na⁺/H⁺ antiporter and V-ATPase genes in gill were measured. The results showed that density and salinity had no significant interaction on Na⁺ and K⁺ concentration of the hemolymph. Na⁺ and K⁺ concentrations in high-salinity group were significantly higher than those in control group. The effects of density and salinity on Na⁺/K⁺ -ATPase activity had significant interaction at 12 h and 24 h. Na⁺/K⁺-ATPase activity in high-salinity group and high-density group was significantly higher than that in control group. SOD activity and MDA content in all experimental groups were significantly higher than those in control group, and density and salinity had significant interaction on SOD activity and MDA content. The expression of Na⁺/H⁺ antiporter and V-ATPase genes in high-salinity group and high-density groups were significantly higher than those in control group. Therefore, high density and salinity performed significant interactive effect on osmotic regulation and antioxidant level of S. constricta. The results provided a theoretical reference for further exploring the response mechanism of marine shellfish to density and salinity.