Chronic inflammation plays a key role in the pathogenesis of myriad complications associated with diabetes and thus anti-inflammatory therapies may ameliorate these complications. Quercus infectoria (Qi) extract has been shown to downregulate inflammatory processes; however, the molecular mechanisms of this anti-inflammatory activity remain unclear. The hypothesis of our study was that Qi extract exerts its anti-inflammatory effect by downregulating the Set7/NF-κB pathway. Bone marrow-derived macrophages (BMM) were treated with high glucose plus palmitate medium (HG/Pa) to simulate the diabetic environment. Compared with control conditions, HG/Pa elevated expression Set7, expression and activity of NF-κB along with expression of several inflammatory cytokines. These changes were associated with increased levels of intracellular reactive oxygen species (ROS). Moreover, similar alterations were demonstrated in BMM derived from mice fed a high fat diet (HFD) compared to those from lean mice, suggesting that HFD-induced changes in BM progenitors persist throughout differentiation and culture. Importantly, Qi extract dose-dependently reduced Set7, p65 and inflammatory cytokine expression relative to vehicle controls in both HG/Pa-and HFD-treated BMM. Finally, macrophages/monocytes isolated from wounds of diabetic mice that were treated with Qi solution exhibited lower expression of the inflammatory cytokines, IL-1β and TNF-α, compared with vehicle treated wounds, demonstrating translation to the in vivo diabetic environment. Taken together, data from this study suggests that Qi downregulates diabetes-induced activity of the Set7/NF-kB pathway.