Southern corn rust (SCR) is a prevalent foliar disease that can lead to severe yield losses in maize. Growing SCR-resistant varieties is the most effective way to control the disease. To identify major quantitative trait loci (QTLs) for SCR resistance, a recombinant inbred line population derived from a cross between CIMBL83 (resistant) and Lx9801 (susceptible) was analyzed. The resistance to SCR had high heritability within the population, and a major QTL on chromosome 4 (qSCR4.01), which can explain 48 to 65% of the total phenotypic variation, was consistently detected across multiple environments. Using a progeny-based fine-mapping strategy, we delimited qSCR4.01 to an interval of ∼770 kb. In contrast to other major QTLs for SCR resistance previously reported on the short arm of chromosome 10, qSCR4.01 is a novel QTL and, therefore, a desirable source of SCR resistance in maize breeding programs.