Southern corn leaf blight is one of the most widespread foliar diseases in maize-producing areas worldwide and can seriously reduce the yield and quality of sweet corn. However, the molecular mechanisms underlying the disease in sweet corn have not been widely reported. In this study, two sweet corn inbred lines, resistant K13 (RK13) and susceptible K39 (SK39), were used to explore the disease resistance mechanism of southern leaf blight. We observed morphological characteristics and assessed the changes in protective enzymatic activity in sweet corn leaves after inoculation of C. heterostrophus. RNA-seq was performed to elucidate the transcriptional dynamics and reveal the key pathways involved in southern leaf blight resistance without pathogens (Mock) and at 1 and 3 days post inoculation (1 and 3 dpi). Differentially expressed genes (DEGs) were identified in the SK39 group (including three pairwise combinations: SK39−0d_vs_SK39−1d, SK39−1d_vs_SK39−3d and SK39−1d_vs_SK39−3d), the RK13 group (including three pairwise combinations: RK13−0d_vs_RK13−1d, RK13−1d_vs_RK13−3d and RK13−1d_vs_RK13−3d), and the SK39_vs_RK13 group (including three pairwise combinations: SK39−0d_vs_RK13−0d, SK39−1d_vs_RK13−1d, and SK39−3d_vs_RK13−3d). In our study, 9455 DEGs from the RK13 group, 9626 from the SK39 group, and 9051 DEGs from the SK39_vs_RK13 group were obtained. Furthermore, 2775, 163, and 185 DEGs were co-expressed at SK39_vs_RK13, RK13, and SK39, respectively. A functional analysis of the DEGs revealed that five pathways—i.e., photosynthesis, plant hormone signal transduction, MAPK signaling pathway, phenylpropanoid biosynthesis, and biosynthesis of secondary metabolites—and transcription factor families play crucial roles in disease resistance. The results from the present study enabled the identification of the JA and SA signaling pathways, which are potentially involved in the response to southern leaf blight in maize. Our findings also highlight the significance of ZIM transcription factors and pathogenesis-related (PR) genes during pathogen infection. This study preliminarily explored the molecular mechanisms of the interaction between sweet corn and C. heterostrophus and provides a reference for identifying southern leaf blight resistance genes in the future.