We aimed to investigate the potential diagnostic value of five serum neuroactive substances in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) complicated with depression. A total of 103 patients with AECOPD were enrolled between August 2020 and August 2021. All patients were assessed using a self-rating depression scale and divided into AECOPD with or without depression groups. Baseline data and serum neuroactive substance levels were compared between the two groups. Logistic regression was used to identify the risk factors. The diagnostic performance of neuroactive substances was evaluated using receiver operating characteristic (ROC) curves. Patients with AECOPD complicated with depression exhibited higher partial pressure of CO2 values and higher chronic obstructive pulmonary disease assessment test (CAT) scores. An elevated proportion of patients with more than two acute exacerbations (AEs) in the previous year was observed in this patient group (all P < 0.001). The CAT score and number of AEs during the previous year were identified as independent risk factors for AECOPD complicated with depression. No significant differences were observed in the levels of aspartic acid and glutamate between the two groups (P > 0.05). Serum ?-aminobutyric acid (GABA) and glycine (Gly) levels were decreased. In contrast, serum nitric oxide (NO) levels were increased in the AECOPD complicated with the depression group (P < 0.05). Serum GABA and Gly levels exhibited a negative correlation, and NO levels positively correlated with the number of AEs in the previous year and the CAT score. The area under the ROC curve values for GABA, Gly, and NO were 0.755, 0.695, and 0.724, respectively. Serum GABA exhibited a sensitivity of 85.1% and a specificity of 58.9%, below the cut-off value of 4855.98 nmol/L. Serum GABA, Gly, and NO may represent potential biomarkers for AECOPD complicated with depression.