Searching for effective therapeutic agents to prevent neurodegeneration is a challenging task due to the growing list of neurodegenerative disorders associated with a multitude of inter-related pathways. The induction and inhibition of several different signaling pathways has been shown to slow down and/or attenuate neurodegeneration and decline in cognition and locomotor function. Among these signaling pathways, a new class of enzymes known as sirtuins or silent information regulators of gene transcription has been shown to play important regulatory roles in the ageing process. SIRT1, a nuclear sirtuin, has received particular interest due to its role as a deacetylase for several metabolic and signaling proteins involved in stress response, apoptosis, mitochondrial function, self-renewal, and neuroprotection. A new strategy to treat neurodegenerative diseases is targeted therapy. In this paper, we reviewed up-to-date findings regarding the targeting of SIRT1 by polyphenolic compounds, as a new approach in the search for novel, safe and effective treatments for neurodegenerative diseases.