Abstract: OBJECTIVE To investigate the protective effect of sodium-glucose cotransporter 2 inhibitors empagliflozin (EMPA) and dapagliflozin(DAPA) on palmitic acid(PA)-induced injury of rat H9c2 cardiomyocytes and its possible mechanism. METHODS H9c2 myocardial cell injury was induced by PA. CCK-8 method was used to screen the optimal dosage of PA, EMPA and DAPA. The protein expression levels of TLR4, p-AKT, p-mTOR, Nrf2 and HO-1 were detected by Western blotting. The expressions of IL-1β, IL-6, TNF-α were detected by ELISA. ROS levels in PA-induced H9c2 cardiomyocytes were determined by fluorescence microscopy and flow cytometry. RESULTS The survival rate of H9c2 cardiomyocytes decreased significantly after treatment of PA 100 μmol·L^-1 for 24 h(P<0.01), the expression of IL-1β, IL-6, TNF-α, TLR4, p-mTOR and ROS were significantly increased(P<0.01), and the protein expression of p-AKT, Nrf2 and HO-1 was significantly decreased(P<0.01). Compared with the model group, the cell survival rate was significantly increased after EMPA and DAPA treatment(P<0.01), the expression of IL-1β, IL-6, TNF-α, TLR4, p-mTOR and ROS levels were significantly decreased(P<0.05 or P<0.01), and the protein expression of p-AKT, Nrf2 and HO-1 was significantly up-regulated(P<0.05 or P<0.01). CONCLUSION EMPA and DAPA have protective effects on PA-induced cardiomyocyte injury, and the mechanism may be related to down-regulation of TLR4 and p-mTOR protein expression, enhancement of AKT protein phosphorylation, activation of Nrf2/HO-1 pathway, and inhibition of ROS generation.