Diet-induced obesity is commonly associated with leptin resistance, and attenuated leptin signaling contributes to the progression of obesity. PAQR3 is a member of the progesterone and AdipoQ receptor (PAQR) family with close homology to adiponectin receptors. We hypothesized that PAQR3 is implicated in the regulation of obesity and energy homeostasis. To address this hypothesis, we fed Paqr3-deleted mice with high-fat diet (HFD), followed by analyses to evaluate obesity, hepatic steatosis, insulin resistance, metabolic rate, and leptin signaling. We found that mice with deletion of Paqr3 are resistant to HFD-induced obesity and hepatic steatosis, accompanied by improvement of insulin resistance and insulin signaling. Paqr3-deleted mice have an increased energy expenditure and physical activity. HFD-induced leptin resistance is reversed by Paqr3 ablation. Overexpression of PAQR3 reduces leptin signaling whereas deletion of Paqr3 enhances leptin signaling in the hypothalamus. In conclusion, this study reveals that PAQR3 has an important physiological function in modulating obesity, energy metabolism, and leptin signaling.