In the present study, we explored the effects of demethylation in a cigarette smoke extract (CSE)-induced mouse emphysema model. Animals were randomly assigned to the control group, CSE group, 5-aza-2′-deoxycytidine (AZA) group, and CSE+AZA group (n = 10 per group). The mitochondrial transcription factor A (mtTFA) promoter methylation increased over 4-fold in the CSE group compared with the control group, which was reversed by AZA. The mtTFA and the cytochrome c oxidase subunit II (COX II) mRNA and protein levels were decreased approximately 3-fold in the CSE group compared with the control group, which was largely restored by AZA. Histological analysis showed that the CSE group exhibited emphysema compared with the control, which was alleviated by AZA. In addition, CSE significantly induced lung cell apoptosis and decreased lung function and lung mitochondrial COX activity, which was mostly restored by AZA. In conclusion, we for the first time provide evidence that demethylation therapy with AZA can effectively improve emphysema, lung function, lung cell apoptosis, and lung mitochondrial COX activity in a CSE-induced mouse emphysema model, which adds fresh insight into the therapeutic potential of demethylating agents in the prevention and treatment of cigarette smoke-induced emphysema.