In this study, combining the thiazole and cinnamoyl groups into the styryl-thiazole scaffold, a series of novel styryl-thiazole hybrids (6a-p) was rationally designed, synthesized, and evaluated by the multi-target-directed ligands strategy as potential candidates for the treatment of Alzheimer's disease (AD). Hybrids 6e and 6i are the most promising among the synthesized hybrids since they are able to significantly increase cell viabilities in A beta 1-42-exposed-human neuroblastoma cell line (6i at the concentration of 50 mu g mL-1 and 6e at the concentration of 25 mu g mL-1 resulted in similar to 34% and similar to 30% increase in cell viabilities, respectively). Compounds 6e and 6i exhibit highly AChE inhibitory properties in the experimental AD model at 375.6 +/- 18.425 mU mL-1 and 397.6 +/- 32.152 mU mL-1, respectively. Moreover, these data were also confirmed by docking studies and in vitro enzyme inhibition assays. Compared to hybrid 6e and according to the results, 6i also has the highest potential against A beta 1-42 aggregation with over 80% preventive activity. The in silico prediction of the physicochemical properties confirms that 6i possesses a better profile compared to 6e. Therefore, compound 6i presents a promising multi-targeted active molecular profile for treating AD considering the multifactorial nature of AD, and it is reasonable to deepen its mechanisms of action in an in vivo experimental model of AD. Novel styryl-thiazole hybrids (6a-p) was rationally designed, synthesized, and evaluated by the multi-target-directed ligands strategy as potential candidates for the treatment of Alzheimer's disease.