Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic metabolic disease that severely affects human health. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE) is a mixture rich in diverse natural flavonoids that exhibits multiple pharmacological properties, including significant anti-inflammatory and antioxidant activities. However, the anti-MASH effects of QFAEE and the underlying mechanisms remain unknown. To investigate the therapeutic effects of QFAEE on MASH and the related mechanisms. The therapeutic effects of QFAEE on hepatic steatosis, inflammatory responses, oxidative stress and apoptotic activity were systematically evaluated in both in vivo and in vitro models of metabolic stress. QFAEE administration significantly reduced hepatic lipid accumulation, inflammatory cell infiltration and liver injury in HFHC diet-fed mice. Combined RNA sequencing and network pharmacology analyses revealed that QFAEE exerted its anti-MASH effects through the modulation of the PPAR signaling pathway. QFAEE ameliorated MASH through PPARα activation and subsequent CPT1A upregulation, which promoted mitochondrial and peroxisomal β-oxidation. Notably, PPARα inhibition promoted hepatic lipid accumulation, inflammation and oxidative stress in hepatocytes, all of which were significantly attenuated by QFAEE treatment. These findings suggest that QFAEE prevents metabolic stress-induced MASH progression by activating PPARα signaling.