Chronic hyperglycemia presents the major etiology of diabetes mellitus and related complications mainly Alzheimer's disease, via the protein glycation and toxic products generated. In the current study, we investigated the eventual protective effect of the methanolic extract of Ceratonia siliqua L. (CsME) against glucose-mediated glycation in serum bovine albumin. The multi-stage glycation markers, namely fructosamines and advanced glycation end products (AGEs) levels were monitored along with measurement of thiol groups; moreover, the in vitro acetylcholinesterase (AChE) inhibition potential was carried out. HPLC was also assessed. Rutin was the main phenolic compound found in CsME. CsME showed a good capacity to inhibit AGEs, fructosamines and protected thiol groups against glycation. CsME exhibited a great AChE inhibition activity. In the present study, CsME prevented glucose-induced protein glycation, it also exhibited a good inhibition of AChE, suggesting its DM complications such as memory troubles related to AD. PRACTICAL APPLICATIONS: Neurodegenerative disorders ranging from memory troubles to Alzheimer's disease present the most diabetes mellitus complications and mainly attributed to protein glycation process. Currently, there is a strong trend to search for efficient natural sources of glycation and acetylcholinesterase inhibitors to replace the synthetic ones, whose secondary effects were shown. The present article tries to justify scientifically the wide use of Ceratonia siliqua L. in Moroccan folk medicine, demonstrating that the methanolic extract of leaves from this species presents a promising source of new natural compounds inhibiting acetylcholinesterase and acting in vitro against glycation generated compounds. Furthermore, for the first time, Rutin was the main phenolic compound found in this extract, these encouraging results should be coupled with further studies to integrate it in pharmaceutical formulations. As such, this paper should be of interest to a broad readership, including those interested in Biochemistry, Phytochemistry, pharmacology, and neurosciences. © 2019 Wiley Periodicals, Inc.