Endothelial dysfunctions, such as pyroptosis, are chronic inflammatory processes with important roles in atherosclerosis. Adiponectin (APN), an adipocyte-derived protein that is abundant in circulation, reportedly protects against atherosclerosis. However, the mechanism underlying its antiatherogenic effect on human aortic epithelial cells remains unknown. In this study, oxidized lipopolysaccharide dose-dependently decreased cell viability and increased lactate dehydrogenase release and pyroptosis in human aortic epithelial cells. Western blot and RT-qPCR assays also showed that APN suppressed activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, as evidenced by cleavage of caspase-1 and downstream secretion of mature interleukin (IL)-1β and IL-18. Silencing of NLRP3 by small interfering RNA remarkably inhibited lipopolysaccharide-induced pyroptosis. Intriguingly, APN led to decreased expression of FoxO4 in human aortic epithelial cells that were exposed to lipopolysaccharide. Moreover, overexpression of FoxO4 inhibited NLRP3-mediated pyroptosis, reversed APN-induced activation of the NLRP3 inflammasome, and reversed pyroptosis in these cells. Specifically, APN reduced propidium-iodide-positive cells, NLRP3 inflammasomes, apoptosis-related speck-like protein containing caspase recruitment domains, and pro-inflammation factors IL-1β and IL-18, all of which was reversed by overexpression of FoxO4. In conclusion, our study suggests that APN might play an essential role in NLRP3 inflammasome-modulated pyroptosis by regulating FoxO4 in human aortic epithelial cells, providing a novel therapy for atherosclerosis.