Coral disease outbreaks are expected to increase in prevalence, frequency and severity due to climate change and other anthropogenic stressors. This is especially worrying for the Caribbean branching coral Acropora palmata which has already seen an 80% decrease in cover primarily due to disease. Despite the importance of this keystone species, there has yet to be a characterization of its transcriptomic response to disease exposure. In this study we provide the first transcriptomic analysis of 12 A. palmata genotypes and their symbiont Symbiodiniaceae exposed to disease in 2016 and 2017. Year was the primary driver of gene expression variance for A. palmata and the Symbiodiniaceae. We hypothesize that lower expression of ribosomal genes in the coral, and higher expression of transmembrane ion transport genes in the Symbiodiniaceae indicate that a compensation or dysbiosis may be occurring between host and symbiont. Disease response was the second driver of gene expression variance for A. palmata and included a core set of 422 genes that were significantly differentially expressed. Of these, 2 genes (a predicted cyclin-dependent kinase 11b and aspartate 1-decarboxylase) showed negative Log2 fold changes in corals showing transmission of disease, and positive Log2 fold changes in corals showing no transmission of disease, indicating that these may be important in disease resistance. Co-expression analysis identified two modules positively correlated to disease exposure, one enriched for lipid biosynthesis genes, and the other enriched in innate immune genes. The hub gene in the immune module was identified as D-amino acid oxidase, a gene implicated in phagocytosis and microbiome homeostasis. The role of D-amino acid oxidase in coral immunity has not been characterized but could be an important enzyme for responding to disease. Our results indicate that A. palmata mounts a core immune response to disease exposure despite differences in the disease type and virulence between 2016 and 2017. These identified genes may be important for future biomarker development in this Caribbean keystone species.