To evaluate the histopathological and immunohistochemical effects of systemically administered nicotine on rat tongue mucosa.Rats were assigned to one of two groups: the experimental group received nicotine systemically (nicotine sulphate 2 mg/kg subcutaneously daily for 28 days), while the rats in the control group were administered physiological saline (1.5 mL subcutaneously for 28 days). All animals were sacrificed at the end of the study, and tongue tissue samples were removed and prepared according to routine histological procedures. Sections were stained with hematoxylin and eosin and observed by light microscopy. Immunoreactivity of tongue mucosa was assessed with E-cadherin, collagen IV, and VEGF expression by immunohistochemical staining.There were significant differences in the average histopathological score between the nicotine-treated and untreated groups. Morphological changes, including inflammatory leukocyte infiltration and cellular desquamation, blood vessel dilation, hemorrhage, and epithelial degeneration, were noted. Further, E-cadherin expression was significantly decreased in the nicotine-treated group versus the untreated group. The nicotine treatment group showed an increase in collagen IV secondary papillae and basal cells.The increased level of VEGF expression in the nicotine-treated group may have affected endothelial cell apoptosis.