Abstract Background l-carnitine (LC) plays an important role in the oxidative/antioxidative balance of different organs. The study has explored the effect of the daily administration of aspartame (ASP) at two different doses for 4 weeks induces oxidative stress, inflammation, and histopathology in the brain of rats. This study also focused on explaining whether l-carnitine (LC) has potential ameliorative effects against pathophysiology induced by ASP in the brain. Adult male Wistar rats were split into six groups as follows: control animals were administered with vehicle, group of ASP at a low dose (ASP-LD) was given 75 mg/kg B.W., high dose of ASP (ASP-HD; 150 mg/kg), animals were treated with LC (10 mg/kg), ASP-LD + LC group and ASP-HD + LC treated rats. Results ASP induced large increments in cytokines of interleukin-6, tumor necrosis factor-α, myeloperoxidase, xanthine oxidase, cyclooxygenase-2, and prostaglandin E2 in a dose-dependent response of the brain. Activities of superoxide dismutase/catalase, glutathione peroxidase, and acetylcholinesterase, besides levels of thiol, glutathione, a brain-derived neurotrophic factor, and neurotransmitters, were decreased in the brain tissue. The inauguration of brain injury by ASP administration was depended on the dose of treatment. Co-administration of LC with ASP significantly reversed and corrected all the abovementioned parameters. Conclusion The data confirm that LC attenuated ASP neurotoxicity by suppressing the inflammation, oxidative stress and improving the neurotransmitters, antioxidants coupled with the histological and cellular structure.