Airway mucus hypersecretion is a vital pathophysiologic feature in chronic obstructive pulmonary disease (COPD) patients in which airflow limitation result, and it is key to strategizing in the management of COPD. To investigate the mechanisms underlying the action of interleukin-6 neutralizing antibody (IL-6 Ab) in attenuating airway mucus hypersecretion in COPD, human and mouse primary bronchial epithelial cells from COPD patients and mice were isolated, human organoid model of trachea was established and all treated with IL-6 and/or IL-6 Ab. The differential expression of Muc5ac and Nrf2 were determined in pDHBE compared to pNHBE cells via high-throughput sequencing of transcriptome. The serum concentration of Muc5ac was significantly elevated and positively correlated with IL-6 in COPD patients using ELISA, and the excessive mucus secretion was observed in the trachea of COPD patients using HE, AB-PAS and IHC staining. The levels of Muc5ac were significantly elevated in the IL-6-treated group, and diminished with IL-6 Ab treatment, both in vitro and in the organoid model using qRT-PCR, WB and IF. The expression levels of protein Muc5ac were significantly reduced in cells transfected with the IL-6 small interfering RNA (siRNA-IL-6), which was in contrast to the levels of protein Nrf2, and the protective effects of IL-6 Ab were inhibited in cells transfected with Nrf2 short hairpin RNA (shRNA-Nrf2). IL-6 Ab significantly attenuated hypersecretion of airway mucus by inducing nuclear translocation of Nrf2 in COPD. These findings indicated that IL-6 Ab may constitute a novel therapeutic agent for IL-6-induced airway mucus hypersecretion by improving airflow limitation in COPD patients.