AbstractAlzheimer's disease (AD) is a multifactorial neurodegenerative disorder attributed to several etiological factors including cholinergic dysregulation, neuroinflammation, oxidative stress, β‐amyloidogenesis, and tauopathy. This demands the search for multitarget drugs, especially of natural sources owing to their pleiotropic activities and low adverse effects. The present study was conducted to investigate the cognitive‐improving potential of Ceratonia siliqua L. (Cs) extract compared with donepezil, an acetylcholinesterase inhibitor, on AD‐like pathological alterations induced by single intracerebroventricular amyloid‐β42 (Aβ42) injection in mice. Aβ42‐injected mice were treated with Cs (100 mg/kg/day, po) with or without methyllycaconitine (MLA; 1 mg/kg/day, ip), an α7‐nAChR antagonist. Aβ42‐injected animals demonstrated an elevation of hippocampal Aβ42, p‐Tau, and acetylcholinesterase. They also showed a decline in phosphorylated levels of Jak2, PI3K, Akt, and GSK‐3β, leading to induction of neuroinflammation and oxidative stress. Noteworthy, Cs improved the histopathological and behavioral variables in addition to mitigating AD hallmarks. It also exerted neuroprotection by reducing NF‐κBp65 and TNF‐α, while elevating Nrf2 and HO‐1, along with stabilizing β‐catenin under the impact of Jak2/PI3K/Akt/GSK‐3β signaling. These beneficial effects of Cs were abrogated by MLA co‐administration signifying the α7‐nAChR involvement in Cs‐mediated effects. Therefore, Cs can ameliorate Aβ42‐induced neurodegeneration by modulating Jak2/PI3K/Akt/GSK‐3β/β‐catenin axis in an α7‐nAChR‐dependent manner.