Alzheimer's disease (AD) is the most common cause of dementia worldwide, normally affecting people aged over 65. Due to the multifactorial nature of this disease, a "multi-target-directed ligands" (MTDLs) approach for the treatment of this illness has generated intense research interest in the past few years. Vanillin is a natural antioxidant and it provides a good starting point for the synthesis of new compounds with enhanced antioxidant properties, together with many biological activities, including β-amyloid peptide aggregating and acetylcholinesterase inhibiting properties. Here we report novel vanillin derivatives, bearing a tacrine or a naphthalimido moiety. All compounds exhibited improved antioxidant properties using DPPH assay, with IC<sub>50</sub> as low as 19.5 μM, FRAP and ORAC assays, with activities up to 1.54 and 6.4 Trolox equivalents, respectively. In addition, all compounds synthesized showed inhibitory activity toward acetylcholinesterase enzyme at μmolar concentrations using the Ellman assay. Computational docking studies of selected compounds showed interactions with both the catalytic anionic site and the peripheral anionic site of the enzyme. Furthermore, these compounds inhibited Aβ<sub>(1-42)</sub> amyloid aggregation using the fluorometric ThT assay, with compound <b>4</b> showing comparable inhibitory activity to the positive control, curcumin. At cellular level compound <b>4</b> (1 μM) showed significant protective effects in neuroblastoma SH-SY5Y cell line when treated with hydrogen peroxide (400 μM). In our opinion, vanillin derivatives could provide a viable platform for future development of multi-targeted ligands against AD.