Wound healing and regeneration in cnidarian species, a group that forms the sister phylum to Bilateria, remains poorly characterised despite the ability of many cnidarians to rapidly repair injuries, regenerate lost structures, or re-form whole organisms from small populations of somatic cells. Here we present results from a fully replicated RNA-Seq experiment to identify genes that are differentially expressed in the sea anemone Calliactis polypus following catastrophic injury. We find that a large-scale transcriptomic response is established in C. polypus, comprising an abundance of genes involved in tissue patterning, energy dynamics, immunity, cellular communication, and extracellular matrix remodelling. We also identified a substantial proportion of uncharacterised genes that were differentially expressed during regeneration, that appear to be restricted to cnidarians. Overall, our study serves to both identify the role that conserved genes play in eumetazoan wound healing and regeneration, as well as to highlight the lack of information regarding many genes involved in this process. We suggest that functional analysis of the large group of uncharacterised genes found in our study may contribute to better understanding of the regenerative capacity of cnidarians, as well as provide insight into how wound healing and regeneration has evolved in different lineages.