The need to maximize the efficiency with which saline-alkaline waters are used for aquaculture is continually increasing due to unabated increases in the global demand for aquaculture products. Here, the effects of chronic saline-alkaline stress on the growth performance, energy consumption, digestion parameters, antioxidant capacity, ion regulation, and non-specific immunity of Phoxinus lagowskii were studied. Fish were exposed to saline environments (10 parts per thousand) varying in the concentration of sodium bicarbonate [5 (T1), 7 (T2), 9 (T3), and 11 mmol L−1 (T4)]. We observed no significant differences in the weight gain and specific growth rate of fish in environments varying in alkalinity concentrations. Exposure to saline-alkaline stress resulted in a decrease in gills LH (lamellar height) and an increase in LT (lamellar thickness) and intestines VH (villous height) in P. lagowskii. The mean corpuscular hemoglobin concentration; mean corpuscular volume; serum albumin and total protein content; the activity of liver acid phosphatase, alkaline phosphatase, and alanine transaminase; and the messenger RNA (mRNA) expression levels of liver TNF-α, which encodes tumor necrosis factor-α, were significantly higher in the T4 group than in the control and other groups. Exposure to saline-alkaline stress also induced a strong antioxidant response that enhanced cellular defenses. Levels of serum glucose and triglycerides, lipase activity, and the expression of Glut-1 in the intestine significantly increased following exposure to saline-alkaline stress. The activity of Na+/K+-ATPase and Ca2+-Mg2+-ATPase and mRNA expression levels of Na+/H+ exchanger isoform 3 in the gills were significantly higher in the saline-alkaline treatments than in the control group. These findings, coupled with the fact that no mortality was observed, suggest that P. lagowskii could be cultured in saline-alkaline waters, and the optimal alkalinity concentration was <11 mmol L−1. Our study is the first to characterize the effects of exposure to saline-alkaline stress on the histological, biochemical, and immunological parameters of P. lagowskii. Our data indicate that P. lagowskii can adapt rapidly to saline-alkaline environmental stress, suggesting that P. lagowskii could be cultivated at commercial scales in saline-alkaline waters.