In Ayurvedic medicine, Salacia reticulata is known to be useful against various metabolic diseases, including diabetes and obesity. In this study, we attempted to clarify the antiobesity mechanism and the safety of S. reticulata in vivo and in vitro. We gave ordinary MF feed, alone or mixed with S. reticulata (0.3 or 1.0%), to Tsumura Suzuki obesity diabetes (TSOD) mice (spontaneous obese type II diabetes model mice) and Tsumura Suzuki non-obese (TSNO) mice (the corresponding reference animals), ad libitum for 2 months. As compared with the TSNO control mice, the TSOD control mice became obese due to fat accumulation and developed various signs of metabolic diseases. The TSOD mouse group receiving S. reticulata showed the following effects: suppression of body weight increase and fat accumulation, alleviation of abnormal lipid metabolism and abnormal glucose tolerance, and suppression of intrahepatic fat accumulation. Also, S. reticulata prevented the mesenteric adipocyte hypertrophy recognized in TSOD mice. In the TSNO controls, the feed containing 1.0% S. reticulata exerted a suppressing effect on body weight increase and fat accumulation, but the feed containing 0.3% S. reticulata did not show any effect at all. In an in vitro experiment using mouse-derived adipocyte precursor 3T3-L1 cells, S. reticulata significantly suppressed fat accumulation in the differentiation induction phase and maturation phase. This suggested that the metabolic disease-preventing effects of S. reticulata, including the antiobesity effect, may involve suppression of differentiation and accumulation in the adipocytes.