A series of novel tacrine-cinnamate and tacrine-cinnamylidene acetate hybrids have been designed, synthesized and evaluated as multitarget compounds for the treatment of Alzheimer´s disease. Results from the assessment of their inhibitory activity against acetylcholinesterase (AChE), antioxidant activity and self-induced β-amyloid (Aβ) aggregation are reported. These hybrid compounds showed promising results: all presented high activity against AChE, with IC50 values between low micromolar and nanomolar range of concentrations. The molecular modeling studies suggested dual interaction with both the catalytic and peripheral sites. Some compounds presented good antioxidant activity (DPPH free radical method) in the low micromolar range, namely the cinnamate derivatives with hydroxyl substituents and extended allylconjugation. Moreover, these compounds showed good neuroprotective effects by rescuing neuroblastoma cells stressed with β-amyloid peptide and hydrogen peroxide. Overall, our results suggest that some of these new hybrids have good potential as multifunctional drug candidates for AD treatment.