Aluminium is a common metallic toxicant that easily penetrates the brain and exerts severe pathological effects e.g., oxidative stress, inflammation and neurodegeneration. Eugenol is a natural phenolic compound possessing numerous therapeutic properties including antioxidant, anti-inflammatory and neuroprotective. The compound has also been reported to interfere with important transcription factors like STAT3 and NF-кB. Thus, the present study intended to explore the therapeutic potential of eugenol in aluminium neurotoxicity. Rats were administered AlCl (100 mg/kg b. wt., orally) and eugenol (200 mg/kg b. wt., orally) alone or in combination for 45 days. The results revealed that AlCl administration increases acetylcholinesterase (AChE) activity, lipid peroxidation (LPO), and protein oxidation (PO) along with decreasing superoxide dismutase (SOD) and catalase (CAT) activities, and glutathione (GSH) content in the cortex and hippocampus regions of the brain. Moreover, AlCl induces neuronal loss and astroglial activation in both brain areas. The study further revealed that AlCl also increases the expression of transcription factors STAT3 and NF-кB in neurons and astrocytes of the cortex and hippocampus. However, co-administration of eugenol with AlCl restored the enzymatic activities of AChE, SOD and CAT, and GSH content, and rescued the cortex and hippocampus from LPO, PO, neuronal loss and astroglial activation. Furthermore, the study reported that eugenol reverses the expression pattern of STAT3 and NF-кB in AlCl-intoxicated rats. In conclusion, the study suggests that eugenol ameliorates oxidative stress, neuronal loss and reactive astrogliosis in aluminium-induced neurotoxicity by inhibiting signalling molecules, STAT3 and NF-кB.