The nonsteroidal anti-inflammatory drug (NSAID) ketoprofen is commonly used as a pain reliever, but its role in mediating the energy metabolism in lipids is unclear. This paper reports for the first time the critical role of ketoprofen in ameliorating white fat browning and alleviating diet-induced obesity. The effects of ketoprofen were evaluated using C57BL/6 mice fed a high fat diet and the expression levels of the target genes and proteins in the lipid metabolisms were determined by quantitative real-time PCR, immunoblot analysis, histopathology study, immunofluorescence, and molecular docking techniques. Ketoprofen induced browning in cultured 3T3-L1 white adipocytes and inguinal white adipose tissue by increasing the expression of core fat browning marker proteins as well as beige-specific genes through COX-2 activation. Ketoprofen also led to the robust activation of brown adipocytes and enhanced brown fat adipogenesis. In addition, ketoprofen elevated lipolysis, thereby increasing mitochondrial biogenesis resulting in higher fat oxidation. Furthermore, the molecular docking and mechanistic study demonstrated the recruitment of beige fat by ketoprofen via mTORC1-p38-mediated activation of the COX-2 pathway. Overall, these results indicate the unique role of ketoprofen in body weight reduction by enhancing thermogenesis, suggesting its therapeutic potential in the treatment of obesity.