Lay summary: Chronic liver fibrosis constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that the neuropeptide cortistatin acts as an endogenous break of hepatic fibrosis and an attractive therapeutic agent in preclinical models of liver damage of different etiologies. The anti-fibrotic effects of cortistatin are directly exerted by regulating the activation and differentiation of hepatic myofibroblasts.