Quercetin, found abundantly in onion peel, has been known to have antioxidant and anti-obesity effects and improves endothelial function. The purpose of this study was to evaluate the effects of a quercetin-rich onion peel extract (OPE) on the inflammatory mediators in overweight and obese women. This study was a randomized double-blind, placebo-controlled study. Thirty-seven healthy overweight and obese women were randomly assigned to two groups, and one group was given a soft capsuled OPE (100 mg quercetin/day, n = 18) and the other group a same capsuled placebo (n = 19) for 12 weeks. Fat mass was measured by bioimpendance method at baseline and after 12 weeks of intervention. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with colorimetric assay kits. The concentrations of leptin, adiponectin, visfatin, tumor necrosis factor (TNF)-α and interleukin (IL)-4 in plasma were determined by using enzyme-linked immunosorbent assay kits. Baseline characteristics of anthropometric indicators and blood metabolic profiles were not significantly different between placebo and OPE groups. Compared with baseline value, both placebo and OPE supplementation significantly decreased the percent of body fat mass and induced plasma adiponectin levels while ALT and AST activities as well as leptin, visfatin, TNF-α, and IL-4 levels in plasma were not significantly different between two groups after 12 weeks of the supplementation. These findings suggest that 12-week supplementation of OPE do not affect modulators of systemic inflammation in overweight and obese women.