The NLRP3 inflammasome is a multimeric protein complex that initiates inflammatory cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. It is implicated in various diseases, including Alzheimer's, Prion, type 2 diabetes, and some infectious diseases. The activation of NLRP3 inflammasome can be triggered by a variety of stimuli, including danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), but the specific regulatory mechanisms remain unclear. Understanding these mechanisms will facilitate the development of specific inhibitors to treat NLRP3-related diseases. This review summarizes the current understanding of the regulatory mechanisms of NLRP3 inflammasome activation and inhibitors that specifically target NLRP3. Key factors include ion fluxes (K⁺ efflux, Ca²⁺ signaling, Na⁺ influx, and chloride efflux), reactive oxygen species (ROS) production, lysosomal destabilization, post-translational modifications of NLRP3, and noncanonical and alternative inflammasome activation. Recent studies have identified several pharmacological inhibitors of NLRP3 inflammasome activation, such as MCC950, CY-09, OLT1177, Tranilast, and Oridonin, which show promising therapeutic potential in animal models of NLRP3-driven diseases. These inhibitors directly target NLRP3 itself and have been shown to be safe and effective, making them promising candidates for treating NLRP3-related inflammatory diseases.The NLRP3 inflammasome is a multimeric protein complex that initiates inflammatory cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. It is implicated in various diseases, including Alzheimer's, Prion, type 2 diabetes, and some infectious diseases. The activation of NLRP3 inflammasome can be triggered by a variety of stimuli, including danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), but the specific regulatory mechanisms remain unclear. Understanding these mechanisms will facilitate the development of specific inhibitors to treat NLRP3-related diseases. This review summarizes the current understanding of the regulatory mechanisms of NLRP3 inflammasome activation and inhibitors that specifically target NLRP3. Key factors include ion fluxes (K⁺ efflux, Ca²⁺ signaling, Na⁺ influx, and chloride efflux), reactive oxygen species (ROS) production, lysosomal destabilization, post-translational modifications of NLRP3, and noncanonical and alternative inflammasome activation. Recent studies have identified several pharmacological inhibitors of NLRP3 inflammasome activation, such as MCC950, CY-09, OLT1177, Tranilast, and Oridonin, which show promising therapeutic potential in animal models of NLRP3-driven diseases. These inhibitors directly target NLRP3 itself and have been shown to be safe and effective, making them promising candidates for treating NLRP3-related inflammatory diseases.