Asthma is a chronic disease related to airway hyper-responsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma and is associated with differentiation of airway epithelia into myofibroblasts via epithelial-mesenchymal transition (EMT) to increase the process of subepithelial fibrosis. There is growing evidence that autophagy modulates remodeling. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we hypothesized that Follistatin-like 1(FSTL1) promotes EMT and airway remodeling by intensifying autophagy. Using transmission electron microscopy (TEM), double membrane autophagosomes were detected in the airways of patients and mice. More autophagosomes were in asthmatic patients and OVA-challenged mice compared to healthy control. The expression of FSTL1 and Beclin1 were upregulated in the airways of asthmatic patients and OVA-challenged mice, accompany with airway EMT and remodeling. In OVA-challenged Fstl1+/- mice, the degree of airway remodeling and autophagy were decreased compared to control mice. The effects of FSTL1 on autophagy and EMT were also tested in 16HBE cells in vitro. Additionally, inhibition of autophagy by using LY294002 and siRNA-ATG5 reduced the FSTL1-induced EMT in 16HBE cells as measured by E-cadherin, N-cadherin and vimentin expression. In line herewith, administration of LY294002 reduced the expression of autophagy, EMT and airway remodeling markers in FSTL1-challenged WT mice. Taken together, our study suggests that FSTL1 may induce EMT and airway remodeling by activating autophagy. These findings may provide novel avenues for therapeutic research targeting the autophagy and FSTL1 pathway which may be beneficial to patients with refractory asthma.