Branched chain amino acids (BCAAs), especially leucine (Leu), have been reported to decrease fat deposition. However, extensive studies have not been conducted to determine whether Leu and isoleucine (Ile) have the same effects in mice fed a high fat diet (HFD). Already obese mice induced by HFD were assigned to the following groups: HFD, HFD + Leu, HFD + Ile, and HFD + Leu + Ile. Chow diet was set as a negative control throughout the study. The results showed that adding Leu, Ile and their combination in drinking water significantly decreased relative white adipose tissue (WAT) weight and serum triglycerides, low-density lipoprotein, free fatty acid, and insulin compared with the HFD control. Insulin sensitivity and hepatic steatosis impaired by HFD were alleviated after Leu or Ile supplementation. Furthermore, lipid metabolism-related genes were modified, and the genes involved in the browning of WAT and beige selective markers were upregulated by dietary supplementation with Leu, Ile and their combination. Intestinal microbiota analysis showed that the ratio of Firmicutes-to-Bacteroidetes was decreased after Leu or Ile treatment. This study indicated that dietary supplementation with Leu or Ile reduced body weight and WAT weight by regulating lipid metabolism-related genes and browning of WAT, providing a new tool in the management of obesity and metabolic disorders.