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Hyperhomocysteinemia (HHcy) was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with HHcy has not been fully elucidated. This study included seven- to nine-week-old C57BL6 male mice induced with HHcy and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of HHcy compared to that in the control group. The apoptotic A549 cells increased as Hcy concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. HHcy exacerbated smoking-induced pulmonary emphysema and ER stress-induced alveolar cell apoptosis. ER stress in alveolar cells was reversed by vitamin B12 and folate supplementation, suggesting that HHcy could be the new therapeutic target to improve smoking susceptibility.