To investigate the changes and clinical significance of serum fatty-acid-binding protein 4 (FABP4) and Interleukin (IL-38) in elderly patients with chronic obstructive pulmonary disease (COPD). Methods From August 2017 to March 2020, 184 elderly patients with COPD were selected as the research objects, including 75 patients with acute exacerbation of COPD (AECOPD group), 109 patients with stable COPD (stable COPD group). And 60 healthy people were selected as the control group. The basic data of the subjects were collected, and the pulmonary function and serum FABP4 and IL-38 levels were detected. Results Compared with the control group, the serum levels of FABP4 and IL-38 in AECOPD group and stable COPD group were significantly increased, while FEV1% pred and FEV1/FVC levels were significantly decreased (P＜0.05). Compared with stable COPD group, the serum levels of FABP4 and IL-38 in AECOPD group were significantly increased, while FEV1% pred and FEV1/FVC levels were significantly decreased (P＜0.05). Pearson correlation analysis showed that serum FABP4 and IL-38 levels were negatively correlated with FEV1% pred and FEV1/FVC levels (P＜0.05). ROC curve analysis showed that the areas under the curve of FABP4 and IL-38 in the diagnosis of AECOPD were 0.813 and 0.807, respectively. When the cutoff values of serum FABP4 and IL-38 were 22.94 ng/mL and 60.82 ng/L, the cut-off sensitivity were 74.31%, 88.99%, and the specificity was 81.33% and 76.01%, respectively. Conclusion The serum levels of FABP4 and IL-38 in elderly patients with COPD are increased, which are closely related to pulmonary function. They could be used as markers for the diagnosis of AECOPD.