Genetic lesions in X-linked Inhibitor of Apoptosis (XIAP) pre-dispose humans to cell death-associated diseases, including severe inflammatory bowel disease and the cytokine storm syndrome hemophagocytic lymphohistiocytosis. Here, we report that patients lacking XIAP can present with heightened levels of both apoptotic and pyroptotic cell death markers in diseased tissue. Using models of XIAP deficiency, we genetically show that only the combined deletion of several cell death modalities abrogates excess cell death and associated inflammasome-driven inflammatory IL-1β activation. Interestingly, our results also reveal that mitochondrial and death receptor apoptosis signalling trigger inflammasome responses via distinct mechanisms, despite both pathways converging of apoptotic caspase-3 and -7. These findings uncouple the mechanisms of cell death and inflammasome activation resulting from extrinsic and intrinsic apoptosis, reveal how XIAP loss can co-opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.