Gambogic acid (GA) is a potential anti-cancer agent with poor water-solubility, whereas heparin has anti-angiogenesis effects with good hydrophilicity. In this study, GA grafted low molecular weight heparin (GA-LMWH) was prepared and self-assembled into micelles in aqueous solution to improve the solubility and antitumor effects against hepatocellular carcinoma. The substitution of GA-LMWH is 27.5 ± 0.2%. The micelles had a mean size of 190.4 ± 10.8 nm, a low critical micelle concentration of 2.4 ± 0.2 μg mL−1, and the highest area under the concentration-time curve and mean retention time in the liver compared to the heart, spleen, lung and kidney (p < 0.05). The targeting efficiency of micelles to the liver is 2.1-times higher than that of the GA solution. GA-LMWH micelles were administered intravenously and significantly improved liver function, decreased cell lesions in hepatic tissue, inhibited the expression of CD105 and prolonged survival time of hepatocellular carcinoma model compared with groups treated with normal saline or GA solution. These results suggest that GA-LMWH micelles may improve anti-cancer effects by targeting the delivery of GA to the liver and enhancing the anti-angiogenesis effect.