Tramadol hydrochloride (TH) is an opioid centrally acting analgesic used to treat moderate to severe acute and chronic pains. Therefore, it became the most prescribed opioid worldwide.In this study, we investigated the neurodegenerative disorders of tramadol in brain tissues and the protective role of royal jelly. Twenty male albino rats allocated into four groups: Group 1,served as a control group, and Group 2, administrated with tramadol at a dose of 20 mg/kg/b. W for 60 days. Group 3:  rats administrated with tramadol at a dose of 20 mg/kg/b. W for 60 days and treated with royal jelly (RJ) in a 100 mg/kg dose. b.w. Group 4: Rats inoculated with royal jelly (RJ) at a dose of 100 mg/kg. b.w. Blood samples were collected for hematological and biochemical analysis. Brain tissues were harvested for neurodegeneration biomarkers detection and histopathological examinations. Administration of tramadol revealed a significant decrease in Hb concentration, RBCs count, PCV %, Lymphocytes %, and platelets number, while WBCS count, Neutrophiles, and monocytes % increased. Also, Tramadol induced a decrease in glucose-6-phosphate dehydrogenase (G6PD) while creatine kinase -BB (CK-BB) and neuron-specific enolase enzymes (NSE) were decreased.Tramadol increased the lipid peroxidation MDA, while total antioxidants capacity (TAC) and glutathione reductase (GSH) concentrations were decreased. Histopathologically, tramadol-induced neurodegenerative changes in brain neurons manifested by acute necrosed neurons with gliosis and vascular congestions. The administration of royal jelly improved the previous deleterious effects by decreasing brain tissue oxidative stress. Tramadol misuse caused neurodegenerative effects and was relieved by RJ administration