Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Recent studies have revealed that nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome, as the core regulatory node of innate immune system, play a key role in the progression from NAFLD to nonalcoholic steatohepatitis and liver fibrosis by integrating the signals of lipotoxicity, oxidative stress and gut-liver axis disorder. In this review, the molecular structure, activation pathway and core regulatory mechanisms of NLRP3 inflammosome were systematically summarized. In addition, small molecular inhibitors, natural compounds and gene editing technologies targeting NLRP3 have shown remarkable efficacy in preclinical models, suggesting its potential as a novel therapeutic strategy for NAFLD. However, current research still faces multiple challenges, such as unclear regulatory mechanism of cell heterogeneity, insufficient research on spatio-temporal dynamics and bottleneck of clinical translation. Subsequently, it is necessary to integrate single-cell and spatial genomics technologies to analyze the cell-specific activation mode of NLRP3 in liver microenvironment. The metabolic-inflammatory interaction network can be elucidated by combining multi-omics data. Allosteric inhibitors or targeted delivery systems can be developed to improve treatment specificity. Through interdisciplinary technological integration and clinical research innovation, NLRP3 inflammatosome-targeted therapy is expected to provide precise and safe intervention protocols for NAFLD patients and promote the translation from basic research to clinical application.