Cigarette smoke (CS) is a leading cause of chronic obstructive pulmonary disease (COPD). Here, we investigated whether the ion channel amplifier nesolicaftor rescues CS-induced mucociliary and ion channel dysfunction. As CS increases the expression of transforming growth factor-beta1 (TGF-β1), human bronchial epithelial cells (HBECs) from healthy donors were used for TGF-β1 and COPD donors (COPD-HBEC) for CS exposure experiments. CS and TGF-β1 induce mucociliary dysfunction by increasing MUC5AC and decreasing ion channel conductance important for mucus hydration. These include cystic fibrosis transmembrane conductance regulator (CFTR) and apical large-conductance, Ca(2+)-activated K(+) (BK) channels. Nesolicaftor rescued CFTR and BK channel dysfunction, restored ciliary beat frequency (CBF), and decreased mucus viscosity and MUC5AC expression in CS-exposed COPD-HBEC. Nesolicaftor further reversed reductions in airway surface liquid (ASL) volumes, CBF, and CFTR and BK conductance, and blocked the increase in extracellular signal-regulated kinase (ERK) signaling in TGF-β1-exposed normal HBECs. Mechanistically, nesolicaftor increased, as expected, not only binding of PCBP1 to CFTR mRNA but also surprisingly to LRRC26 mRNA, which encodes the gamma subunit required for BK function. Similar to nesolicaftor, the angiotensin receptor blocker (ARB) losartan rescued TGF-β1-mediated decreases in PCBP1 binding to LRRC26 mRNA. In addition, the ARB telmisartan restored PCBP1 binding to CFTR and LRRC26 mRNAs to rescue CFTR and BK function in CS-exposed COPD-HBEC. Thus, nesolicaftor and ARBs act on the same target and were therefore neither additive nor synergistic in their actions. These data demonstrate that nesolicaftor and ARBs may provide benefits in COPD by improving ion channel function important for mucus hydration.NEW & NOTEWORTHY Cigarette smoke (CS) increases transforming growth factor-beta1 (TGF-β1) expression that causes mucociliary dysfunction by decreasing ion channel function. In our study, a CFTR amplifier (nesolicaftor) and angiotensin II receptor blockers (losartan and telmisartan) improve CS-induced ion channel dysfunction, by increasing binding of PCBP1 to CFTR and LRRC26 mRNAs. Therefore, nesolicaftor and ARBs, acting on the same target, may provide therapeutic benefits for treating smoking-related diseases.