Bone marrow-derived mesenchymal stem cells (BMSCs) possess potential therapeutic properties for treating patients with chronic obstructive pulmonary disease (COPD), which is characterized by emphysema and obstructive sleep apnea (OSA). However, their effects on overlap syndrome (OS) remain unclear. We investigated the potential therapeutic effects and possible mechanisms of BMSC transplantation in OS rats. To generate the OS model in rats, the animals underwent daily exposure to cigarette smoke and intermittent hypoxia. BMSCs were intravenously injected into rats. At 4 weeks post-transplantation, the severity of emphysema was assessed by lung hematoxylin and eosin (H&E) staining. The levels of oxidative stress and the malondialdehyde (MDA) and superoxide dismutase (SOD) contents in serum and lung were detected. The apoptosis of alveolar septal cells was also detected by TUNEL assay. Finally, we determined the expression of CD31 and VWF in lung tissues by an immunohistochemical (IHC) assay. It was found that BMSCs were able to migrate to the injured lung and aorta tissues. In lung tissues, transplanted BMSCs, some of which had differentiated into endotheliocytes, were found in the alveolar walls. The mean linear intercept (MLI) and pathological scores were higher and the mean alveolar number (MAN) was lower in the OS group than these parameters in the control group. These values were significantly reduced in the OS+BMSC group compared to those in the OS group. The MDA content was decreased and SOD activity was increased in the OS+BMSC group compared to those in the OS group. The apoptotic index of alveolar wall cells in the OS group was higher than that in the OS+BMSC group. The expression levels of CD31 and VWF in alveolar wall cells in the OS group were lower than those in the OS+BMSC group. These results indicate that BMSCs may inhibit the progression of emphysema in the OS model by differentiating into endotheliocytes and suppressing the apoptosis of endotheliocytes and oxidative stress. There is a possibility that the release of growth factors and structural support may be a determinant for the regenerative effects observed following treatment with BMSCs.