Objective To investigate the correlation between the neuronal injury-related biomarkers and delirium in elderly patients after cardiac valve replacement surgery. Methods A total of 109 elderly patients undergoing elective open-heart valve replacement surgery in General Hospital of Western Theater Command from December 2018 to December 2019 were enrolled in the present study. The confusion assessment method for the intensive care unit was utilized to evaluate the delirium in patients after surgery. The serum concentrations of biomarkers for neuronal injury, neuron-specific enolase (NSE) and S100β were measured and compared before and after surgery. The baseline data of all the patients were collected, and univariate and multivariate logistic regression analyses were conducted to verify the correlations between NSE and S100β with delirium, respectively, and the other risk factors for delirium. Results The incidence of delirium was 30.3% (33/109) in the cohort of patients. The serum concentrations of NSE and S100β were significantly increased after surgery (all P<0.01). Multivariate logistic regression analysis indicated that diabetes (OR=1.76,95%CI 1.02-2.61; P=0.04), duration of mechanical ventilation (OR=3.11,95%CI 1.29-7.52; P<0.01), and serum concentrations of NSE (OR=5.94,95%CI 1.53-12.04; P<0.01) and S100β (OR=5.11,95%CI 1.38-10.14; P<0.01) were risk factors for postoperative delirium. Conclusion Neuronal injury biomarkers NSE and S100β are closely correlated with delirium in elderly patients after cardiac valve replacement surgery. The elevated serum concentrations of NSE and S100β might be potent predictors for delirium.