Diet-induced obesity is associated with systemic inflammation, which is considered to originate predominantly from the adipose tissue. Quercetin and resveratrol are two dietary polyphenols that exhibit anti-inflammatory properties and anti-insulin resistance when administered in isolation or combination (CQR). It remains unknown whether CQR reduces high fat diet (HFD)-induced obesity and inflammation in rats. In the current study, 46 male Wistar rats were divided into two groups, one of which was fed a normal diet (ND, 5.4% fat, w/w) and one of which was fed a HFD (45% fat, w/w) for 3 weeks. Following removal of the 12 most obesity-resistant rats from the HFD group, the remaining rats were divided into two sub-groups: A HFD group and a HFD+ CQR group (administered 120 mg/kg/day resveratrol and 240 mg/kg/day quercetin). The results revealed that the HFD+ CQR group had significantly lower body weights at 11 weeks compared with the HFD group and had significantly reduced visceral adipose tissue weights and adipocyte sizes. Serum lipid profiles were also significantly ameliorated in the HFD+ CQR group. CQR attenuated the expression of systemic proinflammatory adipokines, including leptin, tumor necrosis factor-alpha, monocyte chemoattractant protein-1 and interleukin-6. It also reduced the recruitment of mast cells to the epididyotic adipose tissue (EAT). Furthermore, CQR reversed the HFD-induced suppression of 5'-adenosine monophosphate-activated protein kinase alpha 1 (AMPK alpha 1) phosphorylation and sirtuin 1 (SIRT1) expression in EAT. In conclusion, CQR may suppress obesity and associated inflammation via the AMPK alpha 1/SIRT1 signaling pathway in rats fed a HFD.