Excessive activation and proliferation of hepatic stellate cells (HSCs) is the most critical factor in liver fibrosis.Cranberry (Vaccinium macrocarpon) is berry-bearing with potential health benefits. Here, we reported the inhibitory effects of cranberry phytochemicals (CPS) on HSC activation and liver fibrogenesis. The results showed that CPS reduced cell viability and inhibited the TGFβ/Smad signaling pathway of HSCs in vitro. The therapeutic effects of CPS on HSC activation were further linked to the amelioration of CCl4-induced liver fibrosis in rats. CPS treatment reduced liver fibrosis, revived liver function (HYP, MDA, ALB, ALP, ALT, AST, and TBIL), and decreased inflammatory cytokines (IL-1, IL-6, and TNF-α) in a dose-dependent manner. Moreover, the expression levels of the TGFβ/Smad signaling pathway related genes, including TGF-β1, Smad2/3, p-Smad2/3, Col1α1, and α-SMA, were down-regulated by CPS. It is suggested that CPS may inhibit HSC activation and liver fibrosis by reducing the expression of inflammatory cytokines and inhibiting the TGFβ/Smad signaling pathway.