Objective. To explore the correlation of serum IL-18, BDNF, and IL-1β with depression and prognosis after acute exacerbation of chronic obstructive pulmonary disease (COPD). Methods. By means of retrospective analysis, the data of 240 patients at the acute exacerbation of COPD treated in our hospital (February 2018-February 2021) were analyzed. All patients received conventional treatment 1 d after admission, patients’ serological indicators were measured before treatment, and after 30 d of follow-up, the patients were divided into the survival group (SG) and death group (DG) according to their clinical outcomes, the Beck’s Depression Inventory (BDI) scores of the surviving patients were investigated, the correlation of IL-18, BDNF, and IL-1β levels with depression was analyzed by R analytics, and the correlation of IL-18, BDNF, and IL-1β levels with prognosis was analyzed by ROC curve analysis. Results. The results of 30 d follow-up showed that 220 patients survived (91.7%) and 20 patients died (8.3%). Among the surviving patients, 95 patients had depression and 125 patients did not have depression; the BDI scores of the depressed subjects and the nondepressed subjects were 10.35 ± 1.25 points and 2.06 ± 0.76 points, respectively; significant differences in IL-18, BDNF, and IL-1β levels between SG and DG were observed ( P < 0.05 ); significant differences in IL-18, BDNF, and IL-1β levels between the depressed subjects and the nondepressed subjects were observed ( 538.43 ± 19.02 vs. 515.32 ± 9.65 , 7.54 ± 0.56 vs. 12.11 ± 2.41 , and 8.70 ± 0.98 vs. 8.12 ± 0.87 ; P < 0.001 ); among the depressed patients, the IL-18 and IL-1β levels were positively correlative with the BDI scores ( r = 0.781 , r = 0.2583 , P < 0.001 , P = 0.012 ), and the BDNF level was negatively correlative with the BDI scores ( r = − 0.3277 , P = 0.001 ) before treatment; according to the ROC analysis, the AUC (95% CI) of IL-18, BDNF, and IL-1β in predicting prognosis was 0.8770 (0.8281-0.9260), 0.7723 (0.6879-0.8567), and 0.7165 (0.6080-0.8250) ( P < 0.05 ), respectively. Conclusion. In regard to the depression in COPD patients after acute exacerbation, IL18 and IL-1β show positive correlation, and BDNF presents negative correlation. All three indicators have predictive value for patient outcome.