Marine ecosystems are both stressed and threatened by pesticides that are used on land. Nevertheless, research on the impact of pesticides on coral reefs and the underlying mechanisms is still in its infancy. The insecticide chlordecone is a persistent organic pollutant with carcinogenic effects in rats and mice. Chlordecone has been detected in diverse marine organisms in the Caribbean, but unexpectedly, also in French Polynesia. We combined transcriptomic and morphologic analyses of analyses the response of the coral Pocillopora damicornis to chlordecone stress. We compared chlordecone stress with thermal stress to determine a chlordecone-specific response. We found eight transcripts related to the P450-1A or P450-3A families that were specifically overexpressed in response to chlordecone. There was also sequential overexpression of transcripts involved in apoptosis and degradation of cellular matrix proteins. Finally, we report the first observation of chlordecone-induced P. damicornis polyp bail-out. Altogether, these results strongly suggest that apoptosis and expression of genes belonging to the cathepsin family are sequentially regulated processes leading to coenosarc dissociation and loss.