Lipid accumulation inhibition is a pivotal focus for anti-obesity drugs. α-Tocopheryl succinate (TS) is a derivative of α-tocopherol (T) that inhibits lipid accumulation, making it a propitious candidate for an anti-obesity agent. However, cytotoxicity of TS limits its application. Reactive oxygen species produced by TS are responsible for the cytotoxicity, which can be mitigated by T. Herein, we evaluated the effect of a liposomal formulation co-encapsulating TS and T (TS/T-lipo) on obesity. We prepared TS/T-lipo and evaluated the resultant cytotoxicity and lipid accumulation inhibition effect in vitro. TS/T-lipo showed a significant inhibitory effect on lipid accumulation without cytotoxicity. The inhibitory effect on lipid accumulation is likely due to upregulation of Uncoupling Protein 1, which causes lipid consumption. Moreover, we evaluated the effect of TS/T-lipo on a high-fat diet-induced obese mouse model and found that body weight significantly decreased in the TS/T-lipo group without elevation of liver toxicity or blood glucose levels. Additionally, increased glycerol serum levels are suggestive of increased lipolysis upon treatment with TS/T-lipo. Histological analysis supports inhibition of lipid accumulation by treatment with TS/T-lipo. Taken together, this evidence demonstrates that co-administration of TS/T can reduce cytotoxicity and may be a promising candidate for an anti-obesity drug.