Objective Investigate zinc finger protein 36 (ZFP36) and zinc finger protein 36L1 (ZFP36L1) expression in peripheral blood of patients with chronic obstructive pulmonary disease (COPD). Methods Peripheral blood samples were collected from 42 individuals with acute exacerbation of COPD (AECOPD), 21 with stable COPD, and 18 healthy participants. The levels of ZFP36 and ZFP36L1 proteins and mRNA expressions were evaluated using ELISA and qPCR techniques. Difference in expression levels among the three groups was examined. Spearman analysis and receiver operating characteristic (ROC) curve were carried out for assessment of diagnostic and predictive value of FP36 and ZFP36L1 for COPD and AECOPD. Results Compared with the healthy group, ZFP36L1 protein expression was downregulated in the COPD stable group. ZFP36 protein expression was downregulated in the AECOPD group compared with the COPD stable group. Similar differences were observed in mRNA expression levels. ZFP36 and ZFP36L1 levels were negatively correlated with inflammatory markers. ZFP36 levels were positively correlated with ZFP36L1 and lung function, and negatively correlated with smoking index, modified Medical Research Council score, occurrence of respiratory failure during hospitalization, exacerbation frequency within 3 months, and total hospitalizations. The area under the curve (AUC) for diagnosing AECOPD using ZFP36 was 0.980, with sensitivity of 95.2% and specificity of 90.5%. When combined with FEV1%pred, the AUC improved to 0.985, with sensitivity of 92.9% and specificity of 100%. For predicting post-discharge exacerbations in AECOPD when combined with neutrophil-to-lymphocyte ratio (NLR), sensitivity of ZFP36 alone was 66.7% and specificity was 88.9%. The AUCs for diagnosing COPD using ZFP36, ZFP36L1, and interleukin-8 (IL-8) were 0.889, 0.989, and 0.981, respectively. The sensitivities were 61.9%, 90.5%, and 95.2%, and specificities were 100%, 100%, and 94.4%, respectively. Conclusions Peripheral blood ZFP36 has good diagnostic value for AECOPD. Combined with FEV1%pred, it can further increase diagnostic value. As a predictive indicator for frequent exacerbations within 3 months of discharge in COPD patients, its predictive sensitivity and specificity are superior to inflammatory markers such as NLR. ZFP36 exhibits anti-inflammatory effects in AECOPD. Peripheral blood ZFP36L1 has good diagnostic value for COPD.