This study investigated the therapeutic effect of Conocarpus erectus leaves methanolic extract against AlCl3 ‐induced Alzheimer’s disease (AD) in rats comparing with Donepezil‐hydrochloride as a reference drug. The bioactive compounds of C. erectus leaves were isolated and identified by GC/MS and LC‐ESI‐MS analysis. Malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), amyloid‐β‐peptide (Aβ‐peptide), tau protein, acetylcholinesterase (AChE), serotonin (5‐HT), dopamine (DA) and nor‐adrenaline (NE) levels were estimated. The neuromuscular strength, memory behavior and histopathological examination of cerebral cortex region were also conducted. Forty‐three compounds were characterized from the non‐polar fraction of C. erectus L. leaves extract and nineteen compounds were identified from the defatted extract. AlCl3‐ induction caused significant elevation of brain oxidative stress, Aβ‐peptide, tau protein, IL‐6, TNF‐α and AChE levels. A significant decrease in 5‐HT, ND and DA levels were noticed. Additionally, AlCl3 reduced neuromuscular strength and compromised memory function. Treatment of AlCl3‐ induced rats with C. erectuse extract ameliorated these selected parameters by variable degrees. In conclusion, C. erectus protects against AlCl3‐ induced AD in rats through its antioxidant, anti‐inflammatory, and antineutron damage. It could be considered as a new nutraceutical agent for attenuating symptoms associated with Alzheimer's disease.