We recently showed that IL-4-dependent oxidative stress and mitochondrial dysfunction are associated with allergic asthma. IL-4 also induces a prooxidant enzyme, 15-lipoxygenase, which predominantly expresses in asthmatic bronchial epithelium and degrades mitochondria. Esculetin (6,7-dihydroxy-2H-1-benzopyran-2-one), a plant-derived coumarin and immunomodulator, was found to have potent bronchodilating property in carbachol-induced bronchoconstriction and also reduces mitochondrial dysfunction in neurological diseases. In this study, we evaluated its potential in restoring mitochondrial dysfunction and structural changes and anti-asthma property in a mouse model of experimental asthma. In this study, we found that esculetin treatment reduced airway hyperresponsiveness, Th2 response, lung eotaxin, bronchoalveolar lavage fluid eosinophilia, airway inflammation, and OVA-specific IgE. It also reduced the expression and metabolites of 15-lipoxygenase and lipid peroxidation which is an essential prerequisite for mitochondrial dysfunction. Interestingly, esculetin treatment restored the activity of cytochrome c oxidase of electron transport chain in lung mitochondria and expression of the third subunit of cytochrome c oxidase of electron transport chain in bronchial epithelium. It reduced the cytochrome c level and caspase 9 activity in lung cytosol and restored mitochondrial structural changes and lung ATP levels. In addition, esculetin reduced subepithelial fibrosis and TGF-beta1 levels in the lung. These results suggest that esculetin not only restores mitochondrial dysfunction and structural changes but also alleviates asthmatic features.