Deep-sea coral communities are key components of the Gulf of Mexico ecosystem and were adversely affected by the Deepwater Horizon (DWH) oil spill. Coral colonies exposed to oil and dispersant exhibited mortality, damage, and physiological signatures of stress. Understanding how corals respond to oil and dispersant exposure at the molecular level is important to elucidate the sub-lethal effects of the DWH disaster, and reveal broader patterns of coral stress responses. Gene expression profiles from RNAseq data were compared between corals at an impacted site and from a reference site. A total of 1,439 differentially expressed genes (≥ 2-fold) were shared among impacted Paramuricea biscaya colonies. Genes involved in oxidative stress, immunity, wound repair, tissue regeneration, and metabolism of xenobiotics were significantly differentially expressed in impacted corals. Enrichment among the over-expressed genes indicates the corals were enduring high metabolic demands associated with cellular stress responses and repair mechanisms. Under-expression of genes vital to toxin processing also suggests a diminished capacity to cope with environmental stressors. Our results provide evidence that deep-sea corals exhibited genome-wide cellular stress responses to oil and dispersant exposure and demonstrate the utility of next-generation sequencing for monitoring anthropogenic impacts in deep waters. These analyses will facilitate the development of diagnostic markers for oil and dispersant exposure in deep-sea invertebrates and inform future oil spill response efforts.