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Background: Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca 2+ ) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has been applied for the treatment of hepatitis B, but its effect on NAFLD is still unknown, and there is no unified view of Mat on the regulation of ER stress in the previous literature., Methods: The pharmacological effects were studied in high-fat-diet or methionine-choline-deficient diet induced C57BL/6J mice models and in palmitic acid (PA) induced L02 human liver cell model. Calcium fluorescence experiments, computational virtual docking analysis and biochemical assays were used in identifying the locus of Mat., Results: The results showed that Mat-treated mice were more resistant to steatosis in the liver than vehicle-treated mice and that Mat significantly reduced hepatic inflammation, lipid peroxides. The beneficial effect of Mat was associated with suppressing ER stress and restoring mitochondrial dysfunction. Additionally, Mat decreased the PA-induced lipid accumulation, ER stress and cytosolic calcium level ([Ca 2+ ] c ) in hepatocyte cell lines in low and middle dose. However, the high dose Mat did not show satisfactory results in cell model. Calcium fluorescence experiments showed that Mat was able to regulate [Ca 2+ ] c . By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca 2+ ] c via direct inhibition of SERCA., Conclusions: The results showed that the bi-directional regulation of Mat to endoplasmic reticulum at different doses was based on the inhibition of SERCA. In addition, the results also provide a theoretical basis for Mat as a potential therapeutic strategy in NAFLD/NASH.