Background: Electric cigarette smoking (E-smoking) has a growing popularity especially among youth. Its effects on cardiovascular system is not well clarified. Melatonin have beneficial effects in prevention and improving cardiovascular risk factors. So we aim to study E-smoking effects on the thoracic aorta and investigate the possible protection provided by melatonin. Methods: 40 male albino rats were divided equally into four groups; control group: Exposed to no experimental interventions. Melatonin group: Received 5mg/kg/day melatonin orally for 4 weeks. E-smoking group: Exposed to 1ml/day of e-liquid smoke vapor for 1 hour 5consecutive days/week for 4 weeks. E-smoking + melatonin group: Exposed to 1ml/day of e-liquid smoke vapor for 1 hour for 5consecutive days/week and treated with 5mg/kg/day melatonin orally for 4 weeks. Histological sections were stained with hematoxylin and eosin, orcein and masson trichrome stains, and immunostained for Cluster of Differentiation 34 (CD34) and Metalloproteinase-2 (MMP-2). Results: E-smoking group showed decreased tunica media thickness, vacuolated smooth muscles cells, fragmented, atrophied and irregular elastic fibers with pale orcein staining, Strong CD34 and MMP-2 immunoexpressions, also Significant(p<0.001) increment in serum malondialdehyde (MDA) and decrement in glutathione peroxidase (GPx) as compared to control group. In E-smoking+melatonin group, histological structure was mostly preserved with moderate CD34 and negative MMP-2 immunoexpression. Significant decrement in the MDA and increment in GPx serum levels were recorded. Conclusion: E-smoking for 1 month in albino rat is sufficient to initiate aneurysmal pathological changes in the aortic wall. Melatonin provided a protection through inhibition of MMP-2 immunoexpression, its antioxidant and anti-inflammatory actions.