Garlic has shown versatile medicinal activities in the prevention and treatment of diseases such as chronic obstructive pulmonary disease (COPD). However, no individual garlic bioactive components have yet been determined in the COPD treatment effects. In this work, S-allylmercapto-l-cysteine (SAMC) identified in the aged garlic was selected as a model compound to determine its COPD therapeutic potential. The COPD model was established by using lipopolysaccharides (LPS) to stimulate the human airway submucosal gland cell line SPC-A1. Previous studies show that both MUC5AC up-regulation and AQP5 down-regulation play an important role in viscous COPD mucus secretions. The modulation effects of SAMC on LPS-induced MUC5AC and AQP5 productions in SPC-A1 cells were then evaluated. Pretreatment of the SPC-A1 cells with SAMC attenuated MUC5AC secretion and increased AQP5 expression in a dose-dependent manner in the non-cytotoxic concentration range of 20 to 100 μM. Mechanistic studies suggested that SAMC could suppress the accumulation of MUC5AC mRNA and inhibit IχBα degradation and NF-χB p65 translocation. These results suggest that SAMC could be a promising candidate in the prevention and treatment of MUC5AC-associated disorders such as COPD.