OBJECTIVE: To investigate the association between high-sensitivity C-reactive protein (Hs-CRP) levels and the risk of postoperative delirium (POD) following general anesthesia. METHODS: This retrospective cross-sectional study included 644 patients who underwent general anesthesia. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between Hs-CRP and POD, with subgroup analyses used to assess stratified associations. Receiver operator characteristic (ROC) curve analysis was employed to assess the predictive efficacy of Hs-CRP for POD. Restricted cubic spline (RCS) analysis was conducted to explore the linear relationship between the log-transformed Hs-CRP (Log RESULTS: The total population consisted of 644 individuals with a mean age of 64.02 ± 13.20 years, 506 (78.60%) of whom were male, and 114 patients (17.7%) had POD. Compared to the lower Hs-CRP group, patients in the higher Hs-CRP group exhibited higher age, heart rate, white blood cell count, blood urea nitrogen, creatinine, uric acid, fasting glucose, hemoglobin A1c, fibrinogen, D-dimer, and a higher prevalence of CKD, but lower hemoglobin, high-density lipoprotein cholesterol, albumin and estimated glomerular filtration rate. Additionally, the prevalence of POD was higher in the higher Hs-CRP group (24.7% vs. 9.5%, CONCLUSION: Elevated Hs-CRP levels are significantly associated with an increased risk of POD following general anesthesia.