Hepatic fibrosis results from overproduction and excessive accumulation of extracellular matrix (ECM) proteins in hepatocytes. Although the beneficial effects of dendropanoxide (DPx) isolated fromDendropanax morbiferahave been studied, its role as an anti-fibrotic agent remains elucidated. We investigated the protective effect of DPx in BALB/Cmice that received thioacetamide (TAA) intraperitoneally for 6 weeks. Later DPx (20 mg/kg/day) or silymarin (50 mg/kg/day) was administered daily for 6 weeks, followed by biochemical and histological analyses of each group. Hematoxylin and eosin staining of the livers showed TAA-induced hepatic fibrosis, which was significantly reduced in the DPx group. DPx treatment significantly decreased TAA-induced hyperlipidemia as evidenced by the decreased AST, ALT, ALP, γ-GTP and serum TG concentrations and reduced the activities of catalase (CAT) and superoxide dismutase (SOD) activity. ELISA revealed reduced levels of total glutathione (GSH), malondialdehyde (MDA) and Inflammatory factors (IL-6, IL-1β, and TNF-α). Immunostaining showed reduced in collagen-1, α-SMA, and TGF-β1 expression and western blotting showed reduced levels of the apoptotic proteins, TGF-β1, p-Smad2/3, and Smad4. RT-qPCR and Western blotting revealed modifications in SIRT1, SIRT3 and SIRT4. Thus, DPx exerted a protective effect against TAA-induced hepatic fibrosis in the male BALB/Cmouse model by inhibiting oxidative stress, inflammation, and apoptosis via TGF-β1/Smads signaling.