Hyperosmolar stress decreases both mitochondrial respiration and glycolysis in corneal epithelial cells. The hTCEpi cells were cultured in basal media with increasing concentrations of salt. Metabolism was measured using a Seahorse metabolic flux analyzer after six and 24 hours of hyperosmolar culture. (A) At six hours of culture in 450 mOsM, glycolysis was significantly decreased compared to the basal control (**P = 0.021). It was further decreased with 500 mOsM (*P < 0.001). In contrast to this, respiration was not altered after six hours in 450 mOsM but was significantly decreased in 500 mOsM (*P < 0.001, one-way ANOVA, SNK multiple comparison test, n = 3). (B) After 24 hours of culture, glycolysis was severely attenuated in hyperosmolar culture (*P < 0.001, ****P = 0.017, one-way ANOVA, SNK multiple comparison test, n = 3). Mitochondrial respiration was similarly decreased (*P < 0.001, ***P = 0.035, n = 3). (C) There were no differences in the OCR/ECAR ratio at six hours (P = 0.248, one-way ANOVA, SNK multiple comparison test, n = 3). (D) hTCEpi cells expose to increased osmolarity shifted towards a more respiratory phenotype (P = 0.0005, one-way ANOVA, SNK multiple comparison test, n = 3). (E) ATP production was decreased after six-hour culture in 500 mOsM (*P < 0.001, one-way ANOVA, SNK multiple comparison test, n = 3). (F) After 24 hours, ATP production was decreased in both the 450 mOsM and 500 mOsM test groups (*P < 0.001). The greater osmolarity was associated with a greater decrease in ATP production (****P = 0.017, one-way ANOVA, SNK multiple comparison test, n = 3). Data represented as mean ± standard deviation. Graphs representative of a single experiment repeated three times. Number indicates mOsM.