Metabolic associated fatty liver disease (MAFLD) is closely linked to metabolic disorders and lack of effective therapeutic options. Schisandrin A (SA), derived from the traditional Chinese medicinal herb Schisandra, has shown liver-protective properties. SA may counteract MAFLD by modulating endoplasmic reticulum stress (ERS) and inhibiting apoptosis. This study aimed to investigate the protective effects of SA on high-fat diet-induced MAFLD in C57BL/6 mice. The study also sought to elucidate the underlying mechanisms, focusing on the ERS signaling pathway and apoptosis. A MAFLD mouse model was established by feeding mice a high-fat diet. The mice were then randomly divided into the following groups: control, model, SA intervention (various dosages), atorvastatin-treated positive control, and ERS inhibitor combined with SA intervention. serum lipid profiles, liver enzymes, and liver histopathology were assessed. Western blot, immunofluorescence (IF), and TUNEL assay were used to evaluate ERS and apoptosis-related protein expression. SA intervention markedly enhanced serum lipid profiles and reduced liver enzyme levels. The histopathological alterations observed in the model group were significantly mitigated by SA treatment. Western blot analysis revealed that SA effectively modulated the expression levels of proteins associated with ERS and apoptosis. Furthermore, IF and TUNEL assay results substantiated SA’s regulatory influence on ERS and apoptotic pathways. SA effectively improved dyslipidemia and hepatic lipid metabolism abnormalities. It reduced hepatic lipid deposition and pathological damage in MAFLD mice induced by a high-fat diet. The mechanism of action may involve the regulation of the ERS signaling pathway, thereby protecting cells from apoptosis.