Coral diseases are an ongoing and pervasive threat to corals and the reef ecosystems they build. Studies thus far have focused on assessing microbial communities or the identification of specific pathogens. The functional response of the coral metaorganism is at present unknown. To address this gap, we conducted the first metatranscriptomic analysis of the coral host, algal symbiont, and microbial compartments to survey holobiont structure and function in White Plague Disease. Our data show functionally linked responses across compartments, expression of genes associated with viral infection, and increased retroelement activity pointing towards epigenetic deregulation. This study devises an analytical framework for studying coral holobiont function by dissecting organismal response to the contribution of its member species.