Diosmetin, an O-methylated flavone from Caucasian vetch, displays the promising effects on the treatment and prevention of the various diseases, largely through its antioxidant and anti-inflammatory properties. However, its effect on diabetes remains largely unknown. The main purpose of this study is to investigate the potential impacts of diosmetin on insulin resistance, a hallmark of obesity and diabetes, and to evaluate its underlying molecular mechanism. We found that diosmetin markedly attenuated palmitate (PA)-induced insulin resistance in the mature 3T3-L1 adipocytes, evidenced by the elevated levels of phosphorylation of Akt and its downstream AS160, and the increased 2-deoxy-D-glucose uptake when compared with PA treatment alone. Diosmetin was also found to suppress PA-induced endoplasmic reticulum (ER) stress/c-Jun N-terminal kinases (JNKs) signaling and NF-κB signaling pathways. In addition, diosmetin administration significantly decreased the mRNA levels of IL-1β and TNF-α. Furthermore, diosmetin supplementation reversed PA-induced inhibition on adiponectin (ADPN) abundance in both the cells and the culture medium. Given that ER stress is responsible for the activation of NF-κB inflammation signaling pathway and the suppression of ADPN production and secretion, these results revealed that diosmetin mitigates insulin resistance through suppressing ER stress in adipocytes.