Marigold black spot caused by Alternaria tagetica is a major disease that can decrease marigold production by 40%, resulting in serious economic losses. In this study, we identified many genes responsive to A. tagetica in the resistant and susceptible marigold genotypes. Analyses of differentially expressed genes, expression trends, and a weighted gene co-expression network revealed a series of hub genes with key roles in different A. tagetica infection stages. Additionally, 1216 unigenes encoding transcription factors from eight families were differentially expressed between Ts and Ma. Moreover, R genes from various families (e.g., N, NL, RLP, and TNL) were differentially expressed in the two marigold genotypes before and after the inoculation with A. tagetica. Pathway diagrams were used to visualize the leaf transcriptional changes in the two marigold genotypes infected by A. tagetica to clarify the effects of A. tagetica on the expression patterns of genes involved in phosphatidylinositol signaling, plant–pathogen interactions, and plant hormone signal transduction. We identified candidate genes related to disease resistance and generated valuable resources for analyzing the candidate gene functions related to black spot resistance in marigold. The study data may be useful for the molecular marker-assisted screening and breeding of marigold lines with increased disease resistance.