Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic liver injury driven largely by oxidative stress. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a central role in antioxidant defense, and metallothionein-2 (MT2) is a potential downstream target. Methods: Apolipoprotein E knockout mice were fed a high-fat diet (HFD) to establish MASLD model with PNS treatment. Hematoxylin and Eosin Staining (HE) and Oil Red O staining were conducted. Levels of triglyceride (TG), total cholesterol (TC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured. RNA sequencing was conducted, and expression of Nrf2, MT2 was measured. Molecular docking and surface plasmon resonance (SPR) assays were conducted to evaluate interactions between major saponins of PNS and MT2 protein. Results: PNS alleviated lipid accumulation and liver injury in the MASLD model. PNS significantly alleviated oxidative stress and inflammation potentially through Nrf2/MT2 in MASLD mice. Molecular docking revealed that the five major saponins of PNS exhibited favorable binding affinities to MT2. SPR results further demonstrated that ginsenoside Rd may have the most stable binding conformation with MT2. Conclusion: Our study demonstrates that PNS effectively reduces oxidative stress and inflammation in MASLD, potentially through Nrf2/MT2 pathway, and ginsenoside Rd exhibits favorable binding to MT2. These findings provide a novel pharmacological basis for the development of PNS as a potential therapeutic agent for MASLD.