<p>Neurological disorders like Alzheimer’s, Parkinson’s, and stroke involve oxidative stress and inflammation. Current treatments mainly ease symptoms but have side effects. Piceatannol, a natural polyphenol, shows promise as a safer, multi-target neuroprotective agent. This review aims to compile and analyze preclinical evidence on PCN, elucidate its underlying mechanisms, and explore its therapeutic prospects in the management of neurological disorders. A comprehensive literature search was conducted using PubMed/MEDLINE and Google Scholar, incorporating in vitro and in vivo studies that evaluated PCN in relevant models. Findings indicate that PCN exerts neuroprotection through potent antioxidant effects, enhancing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, and activating Nrf2 signaling while suppressing proinflammatory mediators via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway inhibition. It also stabilizes mitochondrial function, prevents neuronal apoptosis by modulating Bcl-2/Bax balance and caspase activity, and mitigates ferroptosis. Furthermore, PCN reduces disease-specific pathological markers such as amyloid-β (Aβ) and acetylcholinesterase (AChE), improving memory, motor performance, and neurobehavioral outcomes. These effects are observed in diverse models, including cerebral ischemia-reperfusion injury (CIRI), subarachnoid hemorrhage (SAH), Alzheimer’s disease, chronic unpredictable stress (CUS), and prion-related neurodegeneration. In conclusion, PCN’s multi-target actions and safe clinical trial position make it a strong candidate for neurodegenerative disease therapy. While preclinical data are compelling, rigorous clinical trials are essential to validate efficacy, optimize dosage, and explore its potential as a standalone or adjunctive treatment for neurological disorders.</p> Graphical Abstract <p></p>