Objective To investigate the relationship between serum cathepsin L (CatL), cathepsin S (CatS), cathepsin B (CatB), inflammatory factors such as interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), COPD assessment test (CAT) scores, and prognosis in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods 224 AECOPD patients admitted to our hospital from January 2022 to December 2022 were selected as the case group, while 62 healthy individuals with normal lung function were selected as the control group. The serum levels of CatS, CatL, CatB, CRP, IL-8, IL-10, TNF-α, and CAT scores were compared between the two groups. Pearson test was used to analyze the correlation between serum CatS, CatL, CatB, inflammatory factors, and CAT scores in AECOPD patients. 224 AECOPD patients were followed up for 28 days, and the number of deaths was counted. Clinical data and laboratory indicators were compared between the survival and death groups. Logistic regression models were used to analyze the influencing factors of AECOPD prognosis.Results The serum CatB levels in the case group were significantly lower than those in the control group (P＜0.05), while CatS and CatL levels were significantly higher than those in the control group (P＜0.05); The serum IL-10 levels in the case group were significantly lower than those in the control group (P＜0.05), and the CRP, IL-8, TNF-α, and CAT scores were significantly higher than those in the control group (P＜0.05). Pearson test showed that serum CatS and CatL in AECOPD patients were positively correlated with CRP, IL-8, TNF-α, and CAT scores (P＜0.05), and negatively correlated with IL-10 scores (P＜0.05); Serum CatB was negatively correlated with CRP, IL-8, TNF-α, and CAT scores (P＜0.05), and positively correlated with IL-10 scores (P＜0.05). Among 224 AECOPD patients, 39 died after 28 days of follow-up. There was no significant difference between the two groups in gender, age, course of COPD, white blood cell count, albumin, drinking history, drinking history, hypertension, diabetes, and coronary heart disease (P＞0.05); Compared with the survival group, the proportion of mechanical ventilation, PaCO2, CatS, and CatL in the death group were significantly increased (P＜0.05), while PaO2 and CatB were significantly reduced (P＜0.05). The logistic regression model showed that mechanical ventilation, PaCO2, CatS, and CatL were risk factors for the prognosis of AECOPD (P＜0.05), while PaO2 and CatB were protective factors (P＜0.05). Conclusion The serum CatS, CatL, and CatB levels in AECOPD patients are closely related to inflammatory factors, CAT scores, and prognosis. The detection of these three levels is helpful in evaluating the condition and prognosis of AECOPD