Exploring independent biomarkers and delineating pathogenic mechanisms could improve the early diagnosis and treatment of chronic obstructive pulmonary disease (COPD). In the present study, a study was conducted to determine the diagnostic potential of miRNA‑101‑3p.1 in identifying stable COPD (SCOPD) and acute exacerbation of COPD (AECOPD) patients and to reveal the molecular mechanism by which miRNA‑101‑3p.1 regulates COPD progression. miRNA‑101‑3p.1 profiles in peripheral blood mononuclear cells of COPD patients were evaluated. Subsequently, receiver operating characteristic curves were created to demonstrate the diagnostic accuracy of miRNA‑101‑3p.1 in discriminating SCOPD and AECOPD. Finally, the molecular mechanism by which miRNA‑101‑3p.1 regulates COPD progression was explored. The present study revealed that patients with COPD, and especially patients with AECOPD, had significantly increased levels of miRNA‑101‑3p.1 and the level of miRNA‑101‑3p.1 was closely correlated with CAT score and FEV1% predicted. Notably, miRNA‑101‑3p.1 accurately discriminated SCOPD and AECOPD. Furthermore, increasing miRNA‑101‑3p.1 promoted cell proliferation and induced the expression of inflammatory cytokines. Mechanistic investigations revealed that miRNA‑101‑3p.1 inhibited the expression of von Hippel‑Lindau tumor suppressor (pVHL) and ubiquitin conjugating enzyme E2 D1 (UBE2D1). pVHL and UBE2D1 co‑upregulated HIF‑1α, and HIF‑1α mediated activation of the EGFR/PI3K/AKT signaling pathway. The present results collectively demonstrated that miRNA‑101‑3p.1 could act as an independent biomarker for the diagnosis of SCOPD and AECOPD, and that miRNA‑101‑3p.1 facilitates COPD progression by activating the EGFR/PI3K/AKT signaling pathway.