Background Electronic cigarettes have gained growing popularity especially among adolescents and young adults. Although the dominant consideration by consumers and the companies claims, whether electronic smoking is indeed a much safer alternative to traditional smoking is hotly debated. Aim To declare the biochemical, histopathological and ultrastructural impact of electronic cigarette exposure on the tissues of respiratory passage. Material and methods Twenty adult male Wistar albino rats were allocated into two groups of 10 animals in each; group I as control group and group II which was exposed to 1 ml/day for one hour of E-liquid involving (18 mg/ml nicotine) for 5 sequential days/ week for 4 weeks. Assessment of markers of oxidative stress; malondialdehyde (MDA) & total antioxidant capacity (TAC) was performed. Specimens of their larynxes and lungs were subjected to histopathological examination with light microscopy (H&E, toluidine blue and orcein stain) with histopathological injury scoring, electron microscopic, histo-morphometric, and immune-histochemical studies of protein α-SMA, p53 and ki-67 Results E-liquid vapors exposed rats exhibited a significant elevation of MDA and suppression in TAC levels in comparison with the control group in all respiratory pathway organs. Microscopic analysis of respiratory epithelium of exposed group revealed hyperplasia, loss of their cilia and vascular dilatation in lamina propria while the lung examination showed thickened alveolar septa, inflammatory infiltrate and congested thick wall blood vessels. The bronchus was lined with multilayered dark stained nuclei epithelium, and there were thickened irregular smooth muscle fibers. Morphometric analysis revealed increase of area percent of elastic fibers in experimental rats’ lungs. Increase of α-SMA and P53 immuno-expression but decrease of Ki-67 immuno-expression in exposed groups were observed when compared to control. Ultrastructural examination showed cilial loss in respiratory epithelium with shrunken type 1 & 2 alveolar cells, with cytoplasmic vacuolations, atypical lamellar bodies and shrunken nuclei. Significant increase of the score of histopathological injury in larynx and lung. Conclusion Exposure to e-liquid with nicotine induces oxidative stress and has adverse impact on respiratory pathway including histo-pathological and ultrastructural disorganization of respiratory epithelium and lung tissues.