Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)–mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of MUC5AC-related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1, as potential key miRNA–mRNA networks regulating CMH in COPD.