Objective Quercetin is an abundant flavonoid with anti-inflammatory action that relies on a wide range of mechanisms of action. It could modify the establishment of inflammation in adipose tissue during obesity. This study investigated the effect of quercetin treatment on obesity, inflammation and insulin sensitivity and its potential molecular mechanisms. Methods The 7 week-old male lean C57BL6/J and ob/ob mice received HF diet (45% energy from fat) for 5 weeks. Quercetin injected intraperitoneally (i.p.) every day for 2 weeks at the dosage of 100 mg/kg body weight after 3 weeks of HF diet feeding. We measured insulin resistance index, adiposity and macrophage infilteration. Results Obese mice presented significantly increased plasma levels of insulin, glucose and IL6, and insulin resistance compared with lean mice. Although quercetin supplementation was not significantly affected on these parameters in both of lean and obese mice with HF diet, it reduced fatty liver and fat weight. Quercetin supplementation significantly increased hepatic GK protein expression and significantly decreased PEPCK protein expression compared with HF diet in lean and obese mice. The mice fed HF with quercetin exhibited a significant reduction in the number of adipose cells expressed per area and a smaller mean cell circumference, radius, and area compared with the mice fed HF in both lean and ob/ob mice. Quercetin supplementation resulted in smaller in distribution of cell size, indicating that the reduction in total fat mass. Quercetin significantly reduced the production of IL-6 in lean mice and macrophage infilteration (F4/80+cells) of epididymal adipose tissue in lean and obese mice. In lean animals, F4/80-expressing cells were uniformly small, dispersed, and rarely seen in aggregates. The fraction of F4/80-expressing cells was greater in obese mice and greatest in the severely obese HF diet fed mice. Ouercetin reduced this macrophage infiltration in lean and obese mice. Conclusion Quercetin significantly reduced the fatty liver and adiposity, which improved hepatic gluconeogenesis. Quercetin was able to inhibit microphage infilteration through maybe cytokine production in adipose tissue.