High‐mobility group box‐1 (HMGB1) is a damage‐associated molecular pattern (DAMP) increased in response to liver injury. Because HMGB1 is a ligand for the receptor for advanced glycation endproducts (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis though RAGE cell‐specific signaling mechanisms. Liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus (HCV) infection, primary biliary cirrhosis (PBC), or alcoholic steatohepatitis (ASH). Hepatic HMGB1 protein expression and secretion increased in five mouse models of liver fibrosis attributed to drug‐induced liver injury (DILI), cholestasis, ASH, or nonalcoholic steatohepatitis (NASH). HMGB1 was up‐regulated and secreted mostly by hepatocytes and Kupffer cells (KCs) following CCl₄ treatment. Neutralization of HMGB1 protected, whereas injection of recombinant HMGB1 promoted liver fibrosis. Hmgb1 ablation in hepatocytes (Hmgb1^ΔHep) or in myeloid cells (Hmgb1^ΔMye) partially protected, whereas ablation in both (Hmgb1^ΔHepΔMye) prevented liver fibrosis in vivo. Coculture with hepatocytes or KCs from CCl₄‐injected wild‐type (WT) mice up‐regulated Collagen type I production by hepatic stellate cells (HSCs); yet, coculture with hepatocytes from CCl₄‐injected Hmgb1^ΔHep or with KCs from CCl₄‐injected Hmgb1^ΔMye mice partially blunted this effect. Rage ablation in HSCs (Rage^ΔHSC) and RAGE neutralization prevented liver fibrosis. Last, we identified that HMGB1 stimulated HSC migration and signaled through RAGE to up‐regulate Collagen type I expression by activating the phosphorylated mitogen‐activated protein kinase kinase (pMEK)1/2, phosphorylated extracellular signal‐regulated kinase (pERK)1/2 and pcJun signaling pathway. Conclusion: Hepatocyte and KC‐derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling through RAGE in HSCs to activate the pMEK1/2, pERK1/2 and pcJun pathway and increase Collagen type I deposition.