Background/objectives: Endostatin is a cleavage product of collagen XVIII and a potent anti-angiogenic factor. Angiogenesis is essential for adipose tissue growth and contributes to liver fibrosis and cancer, suggesting a potential therapeutic role for endostatin in obesity, chronic liver diseases, and hepatocellular carcinoma (HCC). This review article summarises published data on the role and expression of endostatin in obesity, liver injury, and HCC. Methods: PubMed and Google databases were searched using the terms “endostatin and liver”, “endostatin and HCC”, “endostatin and obesity”, and “endostatin and adipose”. Studies published in peer-reviewed journals relevant to this review were considered and reviewed for valuable insights. Results: Endostatin is much more than an inhibitor of angiogenesis; it exerts direct effects on adipocytes and myofibroblasts. Endostatin inhibits adipose tissue growth, and studies using Endostar—a modified form of endostatin approved in China for treating lung cancer—have demonstrated its protective effect in liver fibrosis. However, other studies have shown that endostatin activates hepatic stellate cells, indicating a role in tissue regeneration. Most research on endostatin has focused on cancer, and animal and human studies have shown the benefits of Endostar therapy in HCC. Conclusions: Endostar is a promising treatment for HCC and may also become an attractive drug for liver fibrosis. Hence, angiostatic therapy is not without risks and may only be suitable for selected patients.