Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in Th₁/Th₂ immune response. Increased Th₂ cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through TGF-₁, lead to sub-epithelial fibrosis which is a crucial component of airway remodeling. Synthetic antimalarials have been reported to have immuno-modulatory properties. Mepacrine is known for its reduction of airway inflammation in short term allergen challenge model by reducing Th₂ cytokines and cysteinyl leukotrienes which has an important role in the development of airway remodeling features. So we hypothesized that mepacrine may reduce airway remodeling. For this, extended sub-acute ovalbumin mice model of asthma was developed; these mice showed an increased expression of profibrotic mediators, sub-epithelial fibrosis, goblet cell metaplasia along with airway inflammation, increased Th₂ cytokines, allergen specific IgE, IgG₁, increased cPLA₂ and airway hyperresponsiveness. Presence of intra-epithelial eosinophils and significant TGF-₁ expression in sub-epithelial mesenchymal regions by repeated allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of asthma. However, mepacrine treatment decreased Th₂ cytokines, sub-epithelial fibrosis and alleviates asthma features. These reductions by mepacrine was associated with decrease in levels and expression of TGF-₁ and the reduction in activity, expression of arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that mepacrine might reduce the development of sub-epithelial fibrosis by reducing the arginase and TGF-₁. These effects of mepacrine likely underlie its anti-airway remodeling action in asthma.