Summary Southern leaf blight (SLB), caused by the necrotrophic fungus Cochliobolus heterostrophus , is a major foliar disease of maize ( Zea mays ) world‐wide. A genome‐wide association study was performed to dissect the genetic basis of SLB resistance in maize. Functional validation was performed using mutant and transgenic analyses. Molecular experiments provided preliminary insights into the underlying disease resistance mechanisms. Association analyses identified 14 single nucleotide polymorphisms (SNPs) linked to SLB resistance, 13 of which overlapped with known quantitative resistance loci, highlighting 10 candidate genes. Functional studies confirmed ZmMAPKKK45 , encoding a mitogen‐activated protein kinase kinase kinase (MAPKKK), is the causal gene at a resistance locus on chromosome 3. ZmMAPKKK45 also enhanced resistance to northern leaf blight and gray leaf spot and promotes reactive oxygen species (ROS) accumulation during defense responses. Our results indicate that ZmMAPKKK45 functions outside canonical MAPK cascades and likely enhances disease resistance by upregulating maize respiratory burst oxidase homolog ( ZmRBOH ) genes, thereby increasing ROS production and contributing to broad‐spectrum foliar disease resistance in maize.