Neurodegenerative diseases (NDDs), such as Parkinson’s and Alzheimer’s, are progressive CNS disorders affecting movement, cognition, and other vital functions. Current treatments are mainly palliative and fail to halt disease progression. Given their multifactorial nature, NDDs require therapies that act on multiple targets simultaneously. Flavonoids—natural compounds found in plants—have shown potential in preventing and treating NDDs. Our goal is to develop flavonoid-derivatives capable of simultaneously modulating multiple pharmacological targets relevant to these disorders. We synthesized 18 new compounds (chalcones and dibenzyl acetones) and evaluated their physicochemical properties and targets interactions in-silico. No significant radical scavenging activity was observed (ABTS & DPPH assay). Cytotoxicity in vitro tested on SH-SY5Y culture cells (β-hexosaminidase assay) showed no significant toxicity up to 30 µM. Cholinesterase inhibition (100 µM, Ellman method) showed stronger effects of chalcones over dibenzyl acetones, with butyrylcholinesterase more inhibited than acetylcholinesterase. These results represent an encouraging first step toward the development of multitarget therapies for NDDs. While further studies are needed to expand, the observed in vitro activity highlights the potential of these compounds as promising leads. We aim to contribute to the discovery of more effective and safer treatments that could ultimately improve patients’ quality of life.