Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic cannabinoid 1 receptors (CB1Rs) to promote hepatocyte proliferation in liver regeneration by inducing cell cycle proteins involved in mitotic progression, including Forkhead Box M1. Because this protein is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine treatment induced HCC within 8 months in wild‐type mice but fewer and smaller tumors in CB1R^–/– mice or in wild‐type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome‐wide transcriptome analysis revealed CB1R‐dependent, tumor‐induced up‐regulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor‐promoting genes, including the GRB2 interactome as well as Forkhead Box M1 and its downstream target, the tryptophan‐catalyzing enzyme indoleamine 2,3‐dioxygenase. Increased indoleamine 2,3‐dioxygenase activity and consequent induction of immunosuppressive T‐regulatory cells in tumor tissue promote immune tolerance. Conclusion: The endocannabinoid/CB1R system is up‐regulated in chemically induced HCC, resulting in the induction of various tumor‐promoting genes, including indoleamine 2,3‐dioxygenase; and attenuation of these changes by blockade or genetic ablation of CB1R suppresses the growth of HCC and highlights the therapeutic potential of peripheral CB1R blockade. (Hepatology 2015;61:1615–1626)