To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aβ<sub>1-42</sub> oligomers, was a potent and selective CB<sub>2</sub> ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB<sub>2</sub> inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB<sub>2</sub> receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.