Abstract: Harpagoside (HPG) is an iridoid compound derived from Scrophularia ningpoensis Hemsl. This study aimed to investigate the therapeutic effect of HPG on metabolic dysfunction-associated steatohepatitis (MASH) and elucidate its underlying mechanisms. MASH was induced in mice using a methionine-choline-deficient diet (MCD). The efficacy of HPG in improving MASH was assessed through serum biochemical indexes, liver pathological changes, oxidative stress markers, and inflammatory responses (this experiment was approved by the Laboratory Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine, with approval number PZSHUTCM2305180005). To further explore the mechanism of action, Western blot (WB), quantitative real-time polymerase chain reaction (qPCR), and in vitro cell models were employed. The results demonstrated that HPG (30 and 60 mg·kg^-1) significantly mitigated liver damage (P < 0.05, P < 0.001), reduced hepatic lipid accumulation (P < 0.05, P < 0.001), lowered the elevated non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (P < 0.05, P < 0.01, P < 0.001), alleviated hepatic oxidative stress injury, and suppressed hepatic inflammation in MCD-induced MASH mice (P < 0.05, P < 0.01, P < 0.001). WB and qPCR analyses revealed that HPG promoted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the livers of MCD-fed mice and in AML-12 cells (P < 0.05). Additionally, it reduced the nuclear accumulation of nuclear factor kappa B (NF-κB) in the livers of MCD-fed mice and in THP-1 cells (P < 0.05). Collectively, these findings suggest that HPG improves MASH through alleviating liver oxidative and inflammatory injury by activating Nrf2 antioxidant signaling pathway and inhibiting NF-κB inflammatory signaling pathway.