Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive disorder following surgery and anesthesia, particularly in elderly patients. Isoflurane is a widely used anesthetic agent, which is associated with the development of POCD; however, the precise mechanisms remain unclear. In the present study, aged rats were exposed to 2% isoflurane to establish a POCD model. The expression of PYRIN‑containing Apaf1‑like protein 1 (PYPAF1) was knocked down using a lentivirus containing specific short hairpin RNA. Subsequently, the spatial learning ability of rats was assessed using the Morris water maze. In addition, mRNA and protein expression levels were detected using reverse transcription‑quantitative PCR and western blot analysis, respectively. Immunofluorescence double staining was also used to determine the expression of PYPAF1 and Iba‑1 in the hippocampus. Neural apoptosis was observed using TUNEL‑NeuN double staining. The results revealed that isoflurane exposure impaired the spatial learning ability of rats, while PYPAF1 knockdown alleviated cognitive impairment. In addition, isoflurane exposure induced activation of the PYPAF1 inflammasome, as evidenced by elevated expression of PYPAF1 and apoptosis‑associated speck‑like protein containing a caspase recruitment domain, while silencing of PYPAF1 partially reversed this effect. Furthermore, isoflurane exposure promoted the activation of microglia and caspase‑1, and the secretion of interleukin (IL)‑1β and IL‑18, all of which were alleviated following PYPAF1 silencing. Moreover, isoflurane exposure induced neuronal apoptosis, elevated the levels of Bax and cleaved caspase‑3, and inhibited the expression of Bcl‑2; all of these effects were partially abrogated following PYPAF1 silencing. In conclusion, the results of the present study indicated that PYPAF1 silencing partially abolished isoflurane‑induced cognitive impairment, neuroinflammation and neuronal apoptosis. Therefore, PYPAF1 may be a potential therapeutic target for treatment of POCD.