To investigate the physiological adaptability of the Chinese mitten crab (Eriocheir sinensis) to saline-alkali water environments from the Yellow River estuary, we constructed various gradients of salinity and alkalinity, as well as single-factor stress of salinity (14 and 35 mmol/L) and alkalinity (26 and 55 mmol/L) and combined saline-alkali stress (salinity, 6 and 14 mmol/L; alkalinity, 10 and 26 mmol/L). The crabs were subjected to a continuous saline-alkali stress treatment for 96 h. We examined the survival rate of E. sinensis under saline-alkali stress and the structural changes in the gill tissues (anterior and posterior) and hepatopancreas. Additionally, the activity of the antioxidant enzyme superoxide dismutase (SOD) and concentration of glutathione (GSH) in these tissues were measured. The results showed that E. sinensis from the Yellow River estuary had notable tolerance to sodium chloride salinity and sodium bicarbonate alkalinity. The lethal concentration 50 (LC₅₀) values at 24, 48, 72, and 96 h were 65.90, 55.39, 53.29, and 50.14 mmol/L, respectively, with a safe concentration of 13.97 mmol/L. For alkalinity stress, the LC₅₀ values at 24, 48, 72, and 96 h were 119.4, 86.48, 64.49, and 58.98 mmol/L, respectively, with a safe concentration of 25.96 mmol/L. Histological assessments showed that under saline-alkali stress, the anterior gills suffered more damage than the posterior gills possibly because of their roles in maintaining osmotic balance and ion exchange; thus, the posterior gills showed stronger tolerance to saline-alkaline stress than the anterior gills. Moreover, alkalinity stress caused more severe damage at the tissue level than salinity stress; furthermore, the degree of damage caused by the saline-alkaline interactive stress further exceeded that of the damage caused by the individual stress factors. Under the continuous 96 h-saline-alkali stress, the SOD activity and GSH concentration in the anterior and posterior gills of E. sinensis first increased and then decreased. After 72 h, the SOD activity and GSH concentration significantly decreased to below the initial levels; the SOD activity in the hepatopancreas significantly decreased after 24 h. These results indicate that E. sinensis can activate its antioxidant system to adapt to saline-alkali stress; however, when the intensity of environmental stress exceeds the coping capacity of its antioxidant system, the activity of antioxidant enzymes is suppressed.