Objective(s):We aimed to study the effect of S-nitroso glutathione (SNG) on acute kidney injury (AKI) in septic rats by regulating nucleotide oligomerization domain-like receptor protein 3 (NLRP3).Materials and Methods:Sprague Dawley rats were used to construct the AKI model, and biochemical methods were used to detect the levels of inflammatory factors and anti-oxidant enzymes in renal tissue. We observed the ultrastructural changes of renal tissue by transmission electron microscopy and detected the protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain foci (ASC) and caspase-1 by western-blotting and RT-qPCR.Results:Cecal ligation and puncture induced renal tubular epithelial tissue damage in septic rats, resulting in decreased renal function, increased levels of inflammation and decreased levels of anti-oxidant enzymes in renal tissue, and aggravated mitochondrial damage, significantly decreased mitochondrial density and enzyme complex I/II/III/IV levels (allP<0.001), and increased the protein and mRNA expression of NLRP3, ASC, and caspase-1 (allP<0.001). However, after pretreatment with SNG, the pathological damage of renal tubular epithelial tissue was reduced, the renal function was improved, the level of inflammation in renal tissue decreased and the level of anti-oxidant enzymes increased, the density of mitochondria and the level of enzyme complex I/II/III/IV were significantly increased (allP<0.001), meanwhile the protein and mRNA levels of NLRP3, ASC, and caspase-1 were all decreased significantly (allP<0.05).Conclusion:SNG protects AKI in septic rats by inhibiting NLRP3 inflammasome activation.