Southern corn rust (SCR) is an airborne fungal disease caused by Puccinia polysora Underw. (P. polysora) that adversely impacts maize quality and yields worldwide. Screening for new elite SCR-resistant maize loci or genes has the potential to enhance overall resistance to this pathogen. Using phenotypic SCR resistance-related data collected over two years and three geographical environments, a genome-wide association study was carried out in this work, which eventually identified 91 loci that were substantially correlated with SCR susceptibility. These included 13 loci that were significant in at least three environments and overlapped with 74 candidate genes (B73_RefGen_v4). Comparative transcriptomic analyses were then performed to identify the genes related to SCR infection, with 2,586 and 797 differentially expressed genes (DEGs) ultimately being identified in the resistant Qi319 and susceptible 8112 inbred lines following P. polysora infection, respectively, including 306 genes common to both lines. Subsequent integrative multi-omics investigations identified four potential candidate SCR response-related genes. One of these genes is ZmHCT9, which encodes the protein hydroxycinnamoyl transferase 9. This gene was up-regulated in susceptible inbred lines and linked to greater P. polysora resistance as confirmed through cucumber mosaic virus (CMV)-based virus induced-gene silencing (VIGS) system-mediated gene silencing. These data provide important insights into the genetic basis of the maize SCR response. They will be useful for for future research on potential genes related to SCR resistance in maize.