This study aimed to explore whether the combined application of desflurane and dexmedetomidine (Dex) reduces the occurrence of postoperative neurocognitive disorders (PND) in patients. We selected patients in our hospital who underwent surgery under general anesthesia, and divided them into two groups: Dex and desflurane (Dex + Des) and desflurane (Des) groups. The data of patients were collected and the Mini‐Mental State Examination (MMSE) score was used to assess cognitive status. The blood cell counts were determined preoperatively and on postoperative days 1, 3, and 6, and the percentage of neutrophils and lymphocytes were also recorded. The statistical methods used were the independent‐samples t‐test and the χ2 test. Pearson's correlation was used to analyze the correlation between PND and inflammation. The incidence of PND in the Dex + Des group was lower than that in the Des group. The postoperative MMSE scores in the Dex + Des group were higher than those in the Des group (p = 0.032). The percentage of neutrophils in the Dex + Des group was significantly lower than that in the Des group on the first and third days after surgery (p = 0.007; p = 0.028). The MMSE scores on the first day after surgery were negatively correlated with the multiple changes in white blood counts and the percentage of neutrophils (r = −0.3038 and −0.3330). Dex combined with Des reduced the incidence of PND and reduced the postoperative inflammatory cell counts. Patients undergoing general anesthesia in our hospital were divided into desflurane and dexmedetomidine (Dex + Des) group and a desflurane (Des) group. Preoperative and postoperative MMSE scores, percentage of white blood cells, and neutrophil and lymphocyte counts were determined for postoperative exploration of whether the combined use of Des and Dex reduces the occurrence of PND in patients. The results showed that the combined use of Des and Dex could reduce the occurrence of postoperative PND and was negatively correlated with the postoperative inflammatory cell process.