Tartrazine (TZ), an extensively used azo dye in various industries, has been linked to multiple health risks, including carcinogenicity, allergenicity, phototoxicity, and mutagenicity. Nonetheless, some studies have established its safety at recommended doses. This research focuses on atorvastatin's neuroprotective effects against tartrazine-induced toxicity in the cerebral cortex of male mice. The mice were divided into Four groups: control,atorvastatin, tartrazine-treated, and a combination of tartrazine and atorvastatin, administered over a month. The results demonstrated that tartrazine exposure increased oxidative stress, indicated by elevated malondialdehyde levels and reduced antioxidant defenses (SOD, GSH). This oxidative stress was coupled with pronounced neuronal inflammation, marked by heightened NF-κB and GFAP expression and increased inflammatory cytokines (IL-6, TNF-α, IL-1β). Histopathological analysis revealed neuronal damage, including shrinkage and vacuolation. Tartrazine also triggered apoptosis, raising caspase-3 and Bax levels while decreasing Bcl-2. Conversely, atorvastatin coadministration effectively mitigated these adverse effects, showcasing its antioxidant, anti-inflammatory, and anti-apoptotic properties. It improved oxidative markers, reduced inflammation, and preserved synaptic integrity by maintaining synaptophysin levels. The study underscores atorvastatin's potential as a therapeutic agent to counteract tartrazine-induced prefrontal neurotoxicity, emphasizing its multifaceted protective mechanisms.