<p>The NOD-like receptor protein 3 (NLRP3) inflammasome is among the most extensively studied multiprotein complexes, driving the maturation of pro-interleukin-1β (pro-IL-1β) and pro-IL-18—into their active forms, IL-1β and IL-18, respectively. The activation of the NLRP3 inflammasome is a multifaceted process triggered by a diverse array of stimuli, including pathogens, environmental particles and endogenous stress signals. Previously, NLRP3 inflammasome activation was considered a straightforward two-step process: signal 1, which induces the expression of NLRP3 and proinflammatory cytokines, and signal 2, which promotes the assembly of the inflammasome complex through mechanisms such as ionic fluxes, mitochondrial dysfunction and lysosomal damage. However, more intricate mechanisms have now been elucidated, particularly regarding the ‘priming’ step, involving the regulation of its post-translational modifications. Recent studies have comprehensively identified the core components of the NLRP3 inflammasome complex, its interacting complex partners, and regulatory mechanisms. Here we delve into the current understanding of the NLRP3 inflammasome activation mechanisms and explore its regulatory networks. Enhanced insights into the molecular and signaling pathways controlling this specialized inflammasome activation may pave the way for novel applications of NLRP3 inflammasome regulation to advance human health and prevent numerous diseases linked to the NLRP3 inflammasome.</p>