Chalcones are flavonoids with potential in neurodegeneration. Our aim is to develop chalcone-derived compounds capable of simultaneously modulating multiple pharmacological targets relevant to neurodegenerative disease. From a library of 2′-hydroxychalcones, we identified chalcone 1 (3-chloro-4′,5′-dimethyl-2′-hydroxychalcone), which showed BBB permeability (PAMPA-BBB), no cytotoxicity (SH-SY5Y, ≤10 μM), and compliance with Lipinski’s rule, suggesting drug-likeness. In vitro, chalcone 1 inhibited mouse brain acetylcholinesterase (IC₅₀ = 4.4± 0.8 μM) with low butyrylcholinesterase activity, and reduced Aβ aggregation (51.6± 11.3% at 10 μM). In mice, acute administration (3 mg/kg, i.p.) improved working and long-term memory without affecting anxiety, sedation, or motor activity. Chalcone 1 also selectively inhibited human MAO-B (IC₅₀ = 0.354± 0.084 μM) with negligible MAO-A effect. In a rotenone-induced PD mice model, 7-day treatment reversed motor deficits, reduced oxidative stress, and prevented behavioral impairments, without changes in controls. ThT-based RT-QuIC assays further showed inhibition of α-synuclein aggregation (35.2 ± 7.9 and 58.2 ± 5.8%, reduction in ThT signal at 10 and 100 μM respectively). Altogether, chalcone 1 emerges as a promising multitarget lead for Alzheimer’s and Parkinson’s, combining MAO-B inhibition, anti-cholinesterase, anti-aggregation (Aβ and α-synuclein), antioxidant, neuroprotective, and cognitive-enhancing properties.