Obesity is a major driver of insulin resistance and type 2 diabetes, yet the role of adipocyte MKK3 in this process remains unclear. Here, we investigated whether MKK3 regulates glucose homeostasis specifically in adipose tissue during diet-induced obesity. In human visceral adipose tissue, MKK3 expression positively correlated with body mass index, leptin, and C-peptide, and negatively correlated with HbA1c, suggesting a link between MKK3 expression and metabolic adaptation in obesity. In mice, whole-body Mkk3 deletion worsened insulin sensitivity after HFD- feeding, with impaired insulin-stimulated Akt phosphorylation specifically in white adipose tissue, whereas muscle and liver signaling were largely unaffected. Consistently, adipocyte-specific Mkk3 knockout mice developed a similar insulin-resistant phenotype, supporting an adipocyte-autonomous role for MKK3. Mechanistically, loss of MKK3 reduced particularly p38α and p38β activation and was associated with increased basal mTORC1/p70S6K signaling, enhanced IRS1 Ser307 phosphorylation and defective insulin-stimulated Akt activation in adipocytes. Pharmacological inhibition of mTOR partially restored insulin signaling, indicating that hyperactive p70S6K might contribute to the phenotype. Together, these findings identify the MKK3–p38 axis in adipocytes as a protective pathway against obesity-induced insulin resistance and suggest it may represent a potential therapeutic target in metabolic disease.