Background Obesity and the inflammation associated with it, play a key role in the development of insulin resistance through the release of inflammatory cytokines and free fatty acids and the stimulation of toll-like receptors (TLR). Interleukin-1 receptor-associated kinase (IRAK), which mediates the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, is an important molecule in TLR signaling. The NF-κB pathway can reduce insulin efficacy by increasing the expression of proinflammatory cytokines. There is no safe inhibitor for the NF-κB pathway, and for this reason, the upper mediator of this pathway was selected for investigation. Objectives To determine the effects of an IRAK inhibitor on insulin resistance and serum biochemical factors in high-fat-fed insulin-resistant mice. Methods Insulin resistance was developed in C57BL/6J mice by 12 weeks of a high-fat diet. Subsequently, the IRAK 1/4 inhibitor 1-(2-(4-morpholinyl)ethyl)-2-(3-nitrobenzoylamino)benzimidazole (IRAKi)/or pioglitazone, or both, were administered for a further 2 weeks. After 12 h fasting, blood and tissue samples were collected, insulin and glucose levels were assayed, and the homeostatic model assessment was used to quantify insulin resistance (HOMA-IR). Results The IRAKi decreased blood glucose levels significantly (253 ± 14.3 mg/dL vs 390.1 ± 16.6 mg/dL) and increased insulin sensitivity compared with untreated controls. However, we did not find a synergistic effect of IRAKi with pioglitazone in increasing insulin sensitivity. Conclusion IRAKis can increase insulin sensitivity and their efficacy is comparable to pioglitazone. However, combined administration of pioglitazone and IRAKi had no synergistic effect compared with monotherapy.