Air particulate matter 2.5 (PM) has been demonstrated to exaggerate insulin resistance in both human and animal studies. However, the exact molecular mechanisms remain elusive. This study sought to assess the role of NLRP3 inflammasome in PM exposure-induced insulin resistance and explore the underlying mechanisms. Wild-type (WT), Nlrp3, Tlr4, or Nrf2 mice, on a normal diet or high-fat diet (HFD), were exposed to PM or filtered air (FA) in a whole-body exposure facility. Priming (first signal) and assembly (second signal) of NLRP3 inflammasome activation were assessed by measuring the transcription of Nlrp3/Il-1β and detecting the activity of caspase-1 and secretion of IL-1β. We found PM exposure exaggerated insulin resistance and increased IL-1β production in the HFD-fed WT mice, but not Nlrp3 mice. Gene expressions of Nlrp3 and Il-1β in the lungs and peritoneal macrophages were upregulated in WT mice exposed to PM When stimulated with LPS (first signal) or monosodium urate (second signal), PM exposure was able to enhance the activity of caspase-1 and IL-1β secretion, suggesting that PM may serve as a stimulus of either the first or second signal for NLRP3 inflammasome activation. Effects of PM on caspase-1 activation and IL-1β secretion were partially blocked in Tlr4 mice. Reactive oxygen species (ROS), co-localization of NLRP3 and mitochondria, and secondary lysosomes in macrophages were increased after PM exposure, while deficiency of antioxidant gene Nrf2 in mice significantly enhanced PM-induced secretion of IL-1β. Imaging flow cytometry and transmission electron microscopy demonstrated an engulfment of PM particles by macrophages, while suppression of phagocytosis by cytochalasin D abolished PM-induced transcription of Nlrp3/Il-1β. Our results demonstrated a critical role of NLRP3 inflammasome in PM exaggerated insulin resistance, and multiple pathways in the first and second signals of NLRP3 inflammasome activation may be involved.