The characteristic feature of obesity and insulin resistance is chronic low-grade inflammation. Nod-Like Receptor Pyrin 3 (NLRP3) inflammasome plays a central role in obesity-induced insulin resistance. However, how does Carbenoxolone (CBX) play its role in ameliorating insulin resistance in peripheral tissues of obese mice induced by high-fat diet (HFD) remains unknown. In our study, we explored the molecular mechanism of CBX in improving insulin resistance in liver and skeletal muscle in mice induced by the HFD. Our results revealed that in the CBX group, a significant decrease in fasting blood glucose, insulin and HOMA-IR score were observed. CBX could attenuate intracellular lipid accumulation and inflammation aggravation in liver and skeletal muscle. Besides, treatment with CBX could significantly reduce expressions of p-IκB-α, p-NF-κB, p-IRS-1, NLRP3 and inflammatory factors, increase expressions of p-PI3K and p-AKT. Therefore, CBX could dramatically improve insulin resistance in liver and skeletal muscle in mice induced by the high-fat diet. In conclusions, we demonstrate that CBX has a significant protective effect on diet-induced obesity in mice. The potential mechanisms include inhibiting IκB-α/NF-κB pathway, restricting the production of NLRP3 inflammasome and other inflammatory factors, reducing the expression of p-IRS-1, increasing the expressions of p-PI3K and p-AKT, thus ameliorating insulin resistance in liver and skeletal muscle of high-fat diet mice. Therefore CBX is an active agent against diet-induced obesity and is given the opportunity for the treatment of obesity related diseases.