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Emerging as a promising drug target for Alzheimer's disease (AD) therapy, glycogen synthase kinase 3β (GSK-3β) has garnered attention. This study sought to rigorously scrutinize a compendium of natural compounds retrieved from the ZINC database through pharmacodynamic experiments, employing a 1 H-indazole-3-carboxamide (INDZ) scaffold, to identify compounds capable of inhibiting the GSK-3β protein. Utilizing a multi-step approach, the study involved pharmacophore analysis, followed by molecular docking to select five promising ligands for further investigation. Subsequently, ESMACS simulations were employed to assess the stability of the ligand-protein interactions. Evaluation of the binding modes and free energy of the ligands revealed that five compounds (2a-6a) exhibited crucial interactions with the active site residues. Furthermore, various methodologies, including hydrogen bond and clustering analyses, were utilized to ascertain their inhibitory potential and elucidate the factors contributing to ligand binding in the protein's active site. The findings from MMPBSA/GBSA analysis indicated that these five selected small molecules closely approached the IC50 value of the reference ligand (OH8), yielding energy values of −34.85, −32.58, −31.71, and −30.39 kcal/mol, respectively. Additionally, an assessment of the interactions using hydrogen bond and dynamic analyses delineated the effective binding of the ligands with the binding pockets in the protein. Through computational analysis, we obtained valuable insights into the molecular mechanisms of GSK-3β, aiding in the development of more potent inhibitors. [Display omitted] • We used molecular docking and dynamics to find natural compounds inhibiting gsk-3β, a target for Alzheimer's therapy. • Utilized a multi-step computational approach, including pharmacophore analysis, docking, and ESMACS simulations, to assess ligands. • Identified five compounds with significant inhibitory potential against gsk-3β, based on binding modes and free energy. • Provided insights into gsk-3β inhibition mechanisms through hydrogen bond and clustering analyses of ligand-protein interactions. • Highlighted five small molecules as promising therapeutic candidates for Alzheimer's, with IC50 values close to the reference ligand. [ABSTRACT FROM AUTHOR]