Introduction: Electronic cigarettes (E-cigs) are nicotine delivery devices that work by vaping the E-cigs liquid rather than burning tobacco. It was initially presumed that E-cigs usage was safe. As the popularity of E-cigarettes grows, it's vital to think about their potential dangers and risks. A paucity of studies concerning the hazards of E-cigs was a call to assess the effect of E-cigs on the structure of the submandibular salivary gland (SMG). Aim of the Work: To clarify the structural changes that may take place in rat SMG after E-cigs exposure and the possible amelioration after its cessation. Material and Methods: 30 adult male albino rats were allocated into three equal groups at random. Control group (Group 1). E-cigs exposed group (Group 2): was exposed to E-liquid smoke vapor (1ml/day) for 1 hour for 5 sequential days per week for four weeks. Withdrawal or recovery group (Group 3): was exposed to the same duration and dose of E-liquid smoke vapor as group 2 then left without exposure for another four weeks. At the end of experiment, the SMG were excised and processed for hematoxylin & eosin, Alcian blue-periodic acid Schiff’s stain, Mallory’s trichrome stain and Tumor Necrosis Factor-α (TNF-α) for immunohistochemical study. Also, serum malondialdehyde (MDA) and Glutathione peroxidase-1 (GPx1) enzyme activity were determined. Results: SMG injury was caused by electronic cigarettes in rats, as shown by histological changes in the acini and ducts, including vacuolated cytoplasm, besides increased TNF-α immunoreactivity and its area percentage. Furthermore, E-cigs caused oxidative damage by increasing MDA and decreasing GPx1 enzyme levels. Interestingly, cessation of exposure resulted in some amelioration of the histological and biochemical changes. Conclusion: Electronic cigarettes produce degenerative changes in the histological structure of the submandibular salivary gland and the withdrawal exhibits some degree of improvement.