A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AβO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AβO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment. Display omitted •Novel aryl-acylhydrazone-donepezil hybrids 4c and 4g were synthesized as MTDLs.•Compounds 4c and 4g showed IC50 = 25.4 and 8.65 μM, respectively for AChE inhibition.•4c and 4g showed anti-inflammatory activity against AβO-induced neuroinflammation.•4c and 4g inhibited COX-1/2 and the release of TNF-α in activated microglial cells.•Compound 4c seems to be a promising MTDL drug prototype candidate for AD.