The effectiveness of existing treatments for depression, a complicated mental health condition that affects people all over the world, is limited. The ability of the muscarinic acetylcholine receptor subtype M5 (M5 mAChR) to modulate dopaminergic and cholinergic pathways has made it a unique target in the search for antidepressant drugs. This work used molecular docking to assess the antidepressant potential of fifteen newly created substituted 2-Aminopyrimidine Schiff base derivatives that target the M5 receptor. For the docking simulations, Auto Dock Tools version 1.5.7 was utilized, and the reference antidepressant was fluoxetine. Out of the fifteen compounds, the four derivatives with the highest binding affinities were SSS-14, SSS-13, SSS-01, and SSS-11. In the ortho steric binding pocket of the M5 receptor, these chemicals showed persistent connections with important amino acid residues through hydrophobic contacts, π–π stacking, and hydrogen bonding. The chosen derivatives’ structural characteristics allowed for favourable receptor interaction and spatial orientation. Based on the results, substituted 2-Aminopyrimidine Schiff bases have the potential to be effective antidepressants by selectively modulating the M5 receptor. This study offers a useful computational basis for lead optimization and additional pharmacological validation in the creation of innovative antidepressant treatments