The box jellyfish Chironex fleckeri is one of the most venomous creatures on the planet, envenoming leading to tissue necrosis, extreme pain and in the most severe exposures death within minutes. Despite its rapid and potent action, there is a lack of basic molecular insight into how this venom works. Here we perform the first molecular dissection of a jellyfish venom-induced cell death pathway. We used genome-scale lenti-CRISPR mutagenesis to screen for host components required for cell death after venom exposure. Among host factors required for venom cytotoxicity was the peripheral membrane protein ATP2B1, a calcium transporting ATPase, and genetic or pharmacological targeting of ATP2B1 could prevent venom action and confer long lasting protection. Informatics analysis of host genes required for venom cytotoxicity revealed numerous pathways not previously implicated in cell death, and we have validated many of these genes and pathways. Importantly, we identified a venom antidote that can suppress venom action when added up to 15 minutes after exposure, and this compound could also suppress tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of actions and rapidly identify new medicines.