Objective To investigate the effect of the autophagy activator rapamycin (RAPA) on pyrolysis of neuronal HT22 cells after oxygen and glucose deprivation/ reoxygenation. Methods HT22 cells in logarithmic growth phase were divided randomly into four groups: Control group, Model group, Solvent Control group and RAPA group. Apart from the Control group, cells in the other groups were reoxygenated 24 h after oxygen and glucose deprivation for 6 h. Cell morphology was observed under an inverted microscope. Cell viability was determined by Cell Counting Kit 8 assay, cell damage was determined by the lactate dehydrogenase method, and NLR family pyrin domain-containing 3 (NLRP3) protein expression was detected by immunofluorescence staining. NLRP3, Cleaved Caspase-1, interleukin (IL)-18 and IL-1β expression in cells were detected by Western blot. Results Control cells were bipolar or multipolar with obvious synapses, multiple synapses were woven into a network, and cells showed obvious refractivity. In contrast, cells in the Model and Solvent Control groups showed decreased synapses, the cells were shrunken and rounded, a large number of cells float and fall off, and the number of intercellular connections was decreased. Cell damage was significantly relieved in the RAPA group compared with the Model group. Compared with the Control group, cell viability was significantly reduced and the LDH-leakage rate, NLRP3-positive rate, and intracellular NLRP3, Cleaved Caspase-1, IL-18 and IL-1β protein expression levels increased significantly in the Model group ( P< 0. 01). Compared with the Model group, cell viability was significantly increased and the LDH leakage rate, NLRP3-positive rate, intracellular NLRP3, and Cleaved Caspase-1, IL-18 and IL-1β protein expression levels were all significantly decreased in the RAPA group (P<0. 01). There was no significant difference between the Solvent Control group and the Model group (P> 0. 05). Conclusions RAPA may protect HT22 cells following oxygen and glucose deprivation/ reoxygenation by inhibiting cell pyrolysis.