Obesity results in the progression of metabolic disorders, especially type 2 diabetes (T2DM). Obesity-induced insulin resistance (IR) is a causative factor of T2DM morbidity in obese people. It is generally held by clinicians that IR is caused by adiposity-related inflammation that is mediated by changes in composite ions in the gut microbiome. This experimental study was designed to investigate the effects of Cucumis melo L. (Cucumis) on obesity-induced IR in genetically leptin-deficient Lepob/Lepob mice. Specifically, we examined the anti-inflammatory effects of Cucumis and the effects of Cucumis on the gut microbiota. We evaluated glucose control by measuring FBS, performing the OGTT, quantifying serum IR, calculating the HOMA-IR, and determining the lipid profiles. To see whether inflammation was reduced, we analyzed adipose tissue macrophages as well as monocytes in the blood. We also profiled the gut microbiota to determine whether the ratios of microbial phyla changed. We found that Cucumis improved IR in obese mice and relieved inflammation in adipose tissue and blood. Simultaneously, the microbiota composition ratios changed. In conclusion, administration of Cucumis improved IR by reducing inflammation, thereby changing the gut microbiota composition. Cucumis is thus a promising treatment for obesity-induced insulin resistance and the inflammatory state.