Obesity in itself is a disease condition and a major risk factor in the development of hypertension, dyslipidemia, and hyperglycemia. Therefore, successful strategies for improving obesity and related metabolic risk factors are needed. Role of renin-angiotensin system (RAS) has been implicated in obesity and metabolic dysfunction. Recently, we have shown that AT2R knock-out in female mice caused a greater body weight gain and hyperinsulimia in response to high fat diet (HFD). In the present study, we hypothesize that AT2R activation rescues diet-induced obesity in females. To test this hypothesis, we injected AT2R non-peptide agonist C21 (0.3mg/kg/day i.p) in C57BL6 female mice on HFD for 12 weeks. C21-treatment did not affect the HFD calorie intake (HFD: 937±18 Kcal; C21HFD: 886±37 Kcal) but caused lesser body weight gain compared to control (HFD: 4.4± 0.4g; C21HFD: 3.06± 0.4g). Similar to the body weight gain pattern, gonadal fat weight and adipocyte size were decreased significantly in C21-treated mice on HFD compared to control HFD group (HFD: 4.4± 0.4 g; C21 HFD: 3.06± 0.4g) and (HFD: 6404±161.6μm2 ; C21HFD: 3874±103.2μm2 ) respectively. Moreover, the C21-treated females on HFD had lower levels of plasma insulin, improved glucose tolerance, and decreased plasma free fatty acids and hepatic triglycerides. Western blot revealed that phospho-Ser79-acetyl CoA carboxylase (p-Ser79-ACC-1) was reduced, an index of increased lipogenic activity and decreased β-oxidation process, in both adipose (Adi) and hepatic (Hep) tissues of HFD fed groups (Adi: 86% and Hep: 73% of 100% controls); C21-treatment revered the decrease in p-ser79-ACC-1 in Adi (104% of control) and caused an increase in Hep (122% of control) respectively. The HFD feeding lowered the estradiol level (ND: 38.8±2.6 vs HFD:11.3±1.2ng), which was modestly reversed by C21 treatment (C21HFD:17.4± 1.5ng) in HFD mice. Our results strongly suggest that stimulation of AT2R in female mice positively contribute, predominantly independent of estrogen, to rescue body weight gain and adipocyte size increase in response to HFD. We propose reduced lipogenesis and enhanced lipid β-oxidation as potential mechanisms linked to AT2R action in reducing obesity and its related metabolic disorders in females.