Piceatannol (3,5,3',4'-trans-tetrahydroxystilbene) is a natural analog and a metabolite of resveratrol present in grapes and red wine. Previous studies have reported that piceatannol exerts a broad spectrum of health benefits including antioxidant, anti-inflammatory, chemopreventive, and neuroprotective effects. However, little is known about the hepatoprotective effect of piceatannol against toxin-induced liver fibrosis. Therefore, the objective of this study is to evaluate the protective effect of piceatannol in a mouse model of CCl4-induced hepatic fibrosis. Oral administration of piceatannol significantly improved the hepatic functions of CCl4-treated mice in both therapeutic and preventive models. Additionally, the immunohistochemical staining results revealed that collagen deposition in CCl4-injected mice was significantly reduced by treatment with piceatannol. Moreover, piceatannol remarkably suppressed the expressions of collagen I, α-smooth muscle protein (α-SMA), and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) induced by CCl4. The anti-fibrotic mechanism of piceatannol was associated with the regulation of the transforming growth factor-β (TGF-β)/Smad signaling pathway. Finally, piceatannol also profoundly alleviated CCl4-induced hepatic oxidative damage by elevating the level of glutathione and catalase activity. Altogether, our current findings suggest that piceatannol may serve as a bioactive agent that inhibits or alleviates toxic-induced fibroproliferative diseases, especially in the prevention of liver fibrosis.