The membrane attack complex of complement (MAC), apart from its classical role of lysing cells, can also trigger a range of non-lethal effects on cells, acting as a drive to inflammation. In the present study, we chose to investigate these non-lethal effects on inflammasome activation. We found that, following sublytic MAC attack, there is increased cytosolic Ca²⁺ concentration, at least partly through Ca²⁺ release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP₃R) and ryanodine receptor (RyR) channels. This increase in intracellular Ca²⁺ concentration leads to Ca²⁺ accumulation in the mitochondrial matrix via the ‘mitochondrial calcium uniporter’ (MCU), and loss of mitochondrial transmembrane potential, triggering NLRP3 inflammasome activation and IL-1β release. NLRP3 co-localises with the mitochondria, probably sensing the increase in calcium and the resultant mitochondrial dysfunction, leading to caspase activation and apoptosis. This is the first study that links non-lethal effects of sublytic MAC attack with inflammasome activation and provides a mechanism by which sublytic MAC can drive inflammation and apoptosis.