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A 50‐day feeding experiment was conducted to investigate the effects of dietary protein level (26%, 34%, 43% and 52%) on the survival, growth performance, digestive enzyme activities, antioxidant capacity and body composition in the Chinese mitten crab (Eriocheir sinensis) reared at three salinities (0.5‰, 2‰ and 6‰). Survival rate (SR) showed a clearly decreasing tendency as the salinity elevated. The highest weight gain rate (WGR) was achieved in the treatment of 43% protein at the salinity of 0.5‰ and 2‰, and 26% protein at the salinity of 6‰ (p > 0.05). However, there was no significant interactive effect between dietary protein level and salinity on the SR and WGR of E. sinensis (p > 0.05). As salinity increased, the amylase activity and lipid deposition increased but the Na+/K+‐ATPase activity decreased. The MDA content of E. sinensis was increased at the salinity of 2‰ than the other two salinities by low or moderate dietary protein (26–43% dry diet), but was significantly decreased by high protein (52% dry diet). Correspondingly, the activities of GSH‐Px were increased at the relatively higher protein (43–52% dry diet). The significant interactive effect was only obtained between dietary protein level and salinity on the activities of CAT, GSH‐Px and MDA content of E. sinensis. Dietary protein level had a more obvious positive effects on the EAA deposition at the salinity of 2‰ and 6‰, with the highest contents of essential amino acids (EAAs) achieved by 43% dietary protein. In conclusion, the relatively higher protein could benefit the E. sinensis by inhibiting the lipid peroxidation and increasing the deposition of EAAs at the salinity of 2‰. The elevated activities of amylase could account for the low protein (26%) requirement for E. sinensis reared at the salinity of 6‰. [ABSTRACT FROM AUTHOR]