<p>Our study aims to investigate the potential of artesunate (ART) in improving learning and memory function by down-regulating NLRP3 and consequently affecting pyroptosis levels in the brains of rats with cerebral small vessel disease (CSVD). Initially, Sprague-Dawley (SD) rats were randomly assigned to five groups: the solvent sham operation group, solvent model group, low-dose ART (ART_L) group, medium-dose ART (ART_M) group, and high-dose ART group (ART_H). CSVD rat models were established through bilateral common carotid artery occlusion (BCCAO). Subsequently, the rats were further divided into four groups: the empty plasmid control group (shNC) and three groups receiving NLRP3-shRNA interference plasmids (shNLRP3-1, shNLRP3-2, shNLRP3-3). We recorded animal behaviors and stained nerve cell changes. Hippocampal expression levels of Caspase-1, cleaved caspase-1, IL-18, IL-1β, GSDMD-N, β-actin, and NLRP3 were evaluated in each group. Our findings revealed that ART ameliorated cognitive dysfunction and brain tissue injury in CSVD rats. Moreover, expression levels of cleaved caspase-1, IL-18, IL-1β, GSDMD-N, and NLRP3 in the hippocampus were significantly reduced in the shNLRP3 group, resulting in improved cognitive function in these rats. These results suggest that NLRP3 could be a potential therapeutic target in CSVD development in rats, and modulating its expression might mitigate pathological alterations associated with CSVD. Subsequently, lipopolysaccharide (LPS) was injected into the tail vein, and inflammatory factors in peripheral blood of rats were found to be increased, suggesting that the level of intracranial NLRP3 was increased. In addition, MWM experiment showed that after the increase of NLRP3 expression, the repair effect of ART on learning and memory dysfunction was weakened. ART may enhance cognitive impairment in CSVD rats by downregulating NLRP3 expression in the brain, thereby inhibiting neuronal cell pyroptosis in the hippocampus.</p>