The NLRP3 inflammasome is a critical component of the innate immune system, mediating caspase-1 activation and the secretion of proinflammatory cytokines IL-1β and IL-18 in response to microbial infection and cellular damage. However, its aberrant activation has been linked to several inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, including ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS), and lysosomal damage. This review summarizes the current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events and its regulation by post-translational modifications and interacting partners. The activation of the NLRP3 inflammasome involves a two-signal model, where a priming signal upregulates NLRP3 and pro-IL-1β, and an activating signal triggers the assembly of the inflammasome complex. Post-translational modifications such as ubiquitination, phosphorylation, and nitrosylation play crucial roles in regulating NLRP3 inflammasome activation. Additionally, interacting partners like Nek7, Hsp90, TXNIP, GBP5, PKR, MIF, MARK4, and Nek7 also contribute to the regulation of the NLRP3 inflammasome. Understanding the mechanisms by which these factors integrate to activate the NLRP3 inflammasome is essential for developing therapeutic strategies to modulate its activity in inflammatory disorders.The NLRP3 inflammasome is a critical component of the innate immune system, mediating caspase-1 activation and the secretion of proinflammatory cytokines IL-1β and IL-18 in response to microbial infection and cellular damage. However, its aberrant activation has been linked to several inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, including ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS), and lysosomal damage. This review summarizes the current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events and its regulation by post-translational modifications and interacting partners. The activation of the NLRP3 inflammasome involves a two-signal model, where a priming signal upregulates NLRP3 and pro-IL-1β, and an activating signal triggers the assembly of the inflammasome complex. Post-translational modifications such as ubiquitination, phosphorylation, and nitrosylation play crucial roles in regulating NLRP3 inflammasome activation. Additionally, interacting partners like Nek7, Hsp90, TXNIP, GBP5, PKR, MIF, MARK4, and Nek7 also contribute to the regulation of the NLRP3 inflammasome. Understanding the mechanisms by which these factors integrate to activate the NLRP3 inflammasome is essential for developing therapeutic strategies to modulate its activity in inflammatory disorders.