Lipoprotein lipase (LPL) participates in the development of obesity by regulating triglyceride hydrolysis and fat storage or oxidation. In this study, the anti-obesity effects of lotus seed skin catechins and its mechanisms associated with LPL modulation were demonstrated. In vivo, catechins reduced body weight in high-fat diet-induced obese mice, improved lipid metabolism and antioxidant indices, and modulated LPL activity in adipose and skeletal muscle tissues. The expression of peroxisome proliferator-activated receptor γ (PPARγ) and (angiopoietin-like 4 proteins) ANGPTL4 mRNA and protein was significantly upregulated in epididymal fat depot but downregulated in skeletal muscle tissue. In vitro cell experiments and chromatin immunoprecipitation (ChIP) assays further revealed that the binding sites of PPARγ protein in the ANGPTL4 promoter region were enriched in adipocytes or reduced in skeletal muscle cells in response to catechin treatment. Therefore, lotus seed skin catechins exhibit anti-obesity activity in vivo and in vitro by specifically regulating the activity and expression of LPL in target tissues.