Tramadol is a synthetic opioid that exerts its analgesic influence by acting centrally via inhibiting norepinephrine and serotonin reuptake.  Also, it blocks the propagation of nociceptive signals by activating the μ-opioid receptors. It is a drug of choice in the treatment and prevention of moderate to severe pains. However, various investigations reported that its chronic use is linked to physical and psychological addiction. Tramadol addiction is a serious global health problem. Tramadol has been extensively prescribed, but its negative consequences are still a cause for concern. Therefore, the main aim of this work was to investigate the probable effects of tramadol administration on the cerebellum of male albino rats histologically and morphometrically. Thirty adult male albino rats were allocated randomly into two groups each having 15 rats. The control group (I), was injected intraperitoneally with 1 ml normal saline 0.9%/day for 4 weeks. The second group (II), was injected intraperitoneally with 50 mg/kg/day of tramadol for 4 weeks.  At the end of the experiment, the cerebellum was excised and fixed. Five μm serial sections were cut and prepared for the histological (H&E, silver nitrate) and immunohistochemical staining (GFAP, P53 and Bcl-2). In sections stained with Hx&E ; the following histomorphometric measurements were investigated: (1) The cerebellar cortical layers thickness (2) Purkinje cells' number. Additionally, quantitative immunohistochemistry was performed. Obtained data were subjected to statistical analysis. In Hx&E-stained sections, group (II) displayed thinning of Purkinje cells and granular layers of the cerebellar cortex. The cerebellar folia were separated by wide and deep fissures containing markedly congested blood vessels. The molecular layer exhibited numerous areas of marked degeneration. In the Purkinje cell layer, multiple shrunken and degenerated Purkinje cells with pyknotic nuclei were displayed also associated with numerous areas devoid of Purkinje cells. The granular layer showed less densely packed and some pale granule cells. Silver-stained sections of group (II) displayed marked degeneration of Purkinje cells, multiple vacuolations and sparsely arranged, pale-stained, degenerated granule cells. Group (II) displayed marked GFAP and moderate P53 immune-stained cells in both the cerebellar cortex and white matter. On the other hand, group (II) demonstrated a marked decrease in the immunostaining for Bcl-2 in all layers of the cerebellar cortex and its white matter. In group (II), we detected a statistically non-significant increase in molecular layer thickness and a statistically significant decrease in Purkinje cell and granular layer thickness as compared to group (I). Moreover, the number of Purkinje cells showed a statistically significant decrease in group (II). The surface area percentages of GFAP and P53 immuno-expression in group (II) exhibited an extremely statistically significant rise. However, an extremely statistically significant decrease in the surface area percentage of Bcl-2 immuno-expression was demonstrated in group (II) in comparison with group (I). Tramadol can induce deleterious effects on the cerebellar neurons through upregulation of the GFAP, P53, and, downregulation of Bcl-2. These proteins exert their impacts by inducing inflammation, oxidative stress, and release of several mediators, ER stress and apoptosis.