The assembly of the NLRP3 inflammasome can promote the release of IL-1β/IL-18 and initiate pyroptosis. Accordingly, the dysregulation of NLRP3 inflammasome activation is involved in a variety of human diseases, including gout, diabetes, and Alzheimer's disease. NLRP3 can sense a variety of structurally unrelated pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to trigger inflammation, but the unifying mechanism of NLRP3 activation is still poorly understood. Increasing evidence suggests that intracellular ions, such as K+, Ca2+, and Cl-, have a significant role in NLRP3 inflammasome activation. Here, we review the current knowledge about the role of ionic fluxes in NLRP3 inflammasome activation and discuss how disturbances in intracellular ionic levels orchestrate different signaling events upstream of NLRP3.