Aspartame is an artificial sweetener, used worldwide and is one of the most controversial food additives, regarding its safety. Ongoing research has highlighted the cytotoxic effects of aspartame and the protective potential of sesame oil in mice. Mice of average weight (26 ± 2 g) were exposed to 40 µg/g/day of aspartame with and without sesame oil in various groups (n = 10) for 60 days. Before dissection, mice were acclimatized for one week. Blood was taken for serum biochemistry, meanwhile, liver and kidney tissues were processed for histopathology and to evaluate anti-oxidative and oxidative stress markers from liver and kidney homogenates. Mice body and organ weight increased in the aspartame group as compared to control. Significantly elevated levels of bilirubin, aspartate aminotransferase (AST), Alanine transaminase (ALT), alkaline phosphatase (ALP), Urea and Creatinine were observed in the blood plasma of the aspartame group against control. Histopathological defects showed ballooning hepatocytes, vacuolations, congested central vein and proliferation of Kupffer cells in liver, renal hemorrhage, increased capsular space and glomerulosclerosis in kidneys of aspartame treated mice. In addition to anatomic defects aspartame exposure caused deteriorations in redox balance of the aforementioned tissues by decreasing GSH, SOD, catalase and increasing MDA levels significantly (p ≤ 0.001). Besides, co-administration of sesame oil with aspartame led to significant protection against aspartame-induced toxicities. Hence, aspartame can instigate biochemical and histopathological alterations in albino mice, while sesame oil has the potential to forfend these. [ABSTRACT FROM AUTHOR]