To investigate the clinical significance of microRNAs (miRNAs) in peripheral blood of patients with chronic obstructive pulmonary disease (COPD). Methods Serum miRNA dataset (GSE70080) was downloaded from GEO and differentially expressed miRNAs were identified between COPD and controls. The receiver operating characteristic curve for the miRNA diagnosis performance in COPD were performed. The final target genes were predicted and validated by miRTarbase, Targetscan, PicTar, miRDB. Bioinformatics function analysis was constructed including Gene Ontology analysis, signal pathway analysis, miRNAs-target gene network and the protein=protein interaction (PPI). Results Sixty-two (eight upregulated and fifty-four downregulated) miRNAs were screened out. The area under the receiver operating characteristic curve of up and down regulated miRNAs for the diagnosis of COPD were 0.938 and 0.969, respectively. The target genes of miRNA were mainly enriched in WNT, MAPK, NF-κB signaling pathway. Through the miRNAs-target gene network construction, the hub genes were SLC4A8, found to be potentially modulated by seven miRNAs. ACVR1B, ACVRL1, KRT2, KRT74 and KRT82 maybe play a core role in PPI network. Conclusion Significant differential expressed miRNAs exist in the serum of patients with COPD, and they may be involved in the pathogenesis of COPD through a serial of mechanisms.