Signaling pathways mediated by the mechanistic target of rapamycin (mTOR) play key roles in aging and age-related diseases. As a downstream protein of mTOR, transcription factor EB (TFEB) controls lysosome biogenesis and cellular trafficking, processes that are essential for the functions of phagocytic cells like the retinal pigment epithelium (RPE). In the current study, we show that a naturally occurring polyphenolic compound, quercetin, promoted TFEB nuclear translocation and enhanced its transcriptional activity in cultured RPE cells. Activated TFEB facilitated degradation of phagocytosed photoreceptor outer segments. Quercetin is a direct inhibitor of mTOR but did not influence the activity of Akt at the tested concentration range. Our data suggest that the dietary compound quercetin can have beneficial roles in neuronal tissues by improving the functions of the TFEB-lysosome axis and enhancing the capacities of cellular degradation and self-renewal.