Aspartame (Laspartyl-L-phenylalanine methyl ester, ASP) is considered as non-nutritive and non-caloric artificial sweetener consumed by more than two hundred million people worldwide. It has been recorded to be safe by World Health Organization. However, numerous publications have concluded that ASP is a genotoxic and carcinogenic sweetener. Silymarin is a polyphenolic compound obtained from the seeds and fruits of Silybummarianum. Silymarin has been shown to possess antioxidant and anti-inflammatory activities. The current study aimed to evaluate the effect of ASP consumption (250 mg/kg b. wt/day for 90 d) on the chromosomal aberration (CA) frequency, mitotic index percentage (MI%), some biochemical parameters, oxidative/anti-oxidative status in different tissues and Tumor Necrosis Factor-α (TNF-α) in addition to the possible ameliorative role of silymarin (50 mg/kg b. wt/day for 90 d) against ASP-induced toxicity in male albino rats. The present results have confirmed that ASP is able to induce significant increase in the frequency of CA and MI%, blood glucose level, liver, kidney and lipid function tests, Malondialdehyde (MDA) level and serum TNF-α level. Meanwhile, Glutathione reduced level (GSH), Glutathione–S-transferase (GST) and catalase activity (CAT) were decreased by ASP administration. Recovery group showed slight enhancement in all parameters but remained significant as compared to the control group. Co-administration of ASP with silymarin showed greater improvement than the recovery group. Conclusion: Silymarin have an ameliorative role against chromosomal aberrations and MI%, biochemical oxidative stress, inflammatory changes in blood and different tissues induced by ASP administration.