Inflammasomes are multiprotein complexes that play a critical role in the regulation of inflammation and the inflammatory responses against pathogens. NLRP3 (NOD-, LRR-and pyrin domain-containing protein 3) is among the molecules involved in the homonymous and well-studied NLRP3 inflammasome that accounts for the release of the pro-inflammatory cytokines interleukin (IL) 1-β and 18. Two signals (priming and activation) that include molecular and cellular events lead to the activation of the complex; the main events involved during the activation phase are ionic fluxes, mitochondrial dysfunction, and lysosomal damage. Calcium mobilisation belongs to the signalling events of ionic fluxes associated with the complex assembly initiation. Although no consensus has been established regarding the ionic Ca2+ fluxes and the exact mechanisms contributing to NLRP3 activation, several sources agree that Ca2+ mobilisation homeostasis is essential for the canonical function of the NLRP3 inflammasome, and other cellular processes associated with it. This systematic review aimed to determine the factors and mechanisms related to Ca2+ mobilisation contributing to inflammasome activation, examine NLRP3-associated pathologies, and propose potential therapeutic targets. The literature sources found were evaluated using the CASP tool. The obtained information revealed an intertwined relation of Ca2+ flux with the calcium-sensing receptor, reactive oxygen species (ROS) generation, lysosome rupture, Ca2+-permeable channels and K+ efflux contributing to NLRP3 inflammasome activation. The summarised knowledge in this review has led to the proposal of future studies through references to different NLRP3-related diseases such as Alzheimer’s and diabetes type II, while potential therapeutic targets were also discussed.