© 2019 Background: Abnormal chloride (Cl−) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl− secretion in nasal epithelium. Methods: Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR−/−], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro–optical coherence tomography (μOCT). Mechanisms underlying transepithelial Cl− transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis. Results: RGAE (at 30μg/mL of ginsenosides) significantly increased Cl− transport [measured as change in short-circuit current (ΔISC = μA/cm2)] when compared with control in WT and CFTR−/− MNSE (WT vs control = 49.8±2.6 vs 0.1+/−0.2, CFTR−/- = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔISC attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/− 807.7 pA) over uridine 5-triphosphate (3524.1 +/− 292.4 pA) or RGAE alone (465.2 +/− 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/−0.3 μm vs control, 3.9+/−0.09 μm; 10.4+/−0.3 Hz vs control, 7.3 ± 0.2 Hz; p < 0.0001) in MNSE. Conclusion: RGAE augments ASL depth and CBF by stimulating Cl− secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis.