A hallmark in prion diseases is the conformational transition of the cellular prion protein (PrPC) into a pathogenic conformation, designated scrapie prion protein (PrPSc), which is the essential constituent of infectious prions. Here, we show that epigallocatechin gallate (EGCG) and gallocatechin gallate, the main polyphenols in green tea, induce the transition of mature PrPC into a detergent-insoluble conformation distinct from PrPSc. The PrP conformer induced by EGCG was rapidly internalized from the plasma membrane and degraded in lysosomal compartments. Isothermal titration calorimetry studies revealed that EGCG directly interacts with PrP leading to the destabilizing of the native conformation and the formation of random coil structures. This activity was dependent on the gallate side chain and the three hydroxyl groups of the trihydroxyphenyl side chain. In scrapie-infected cells EGCG treatment was beneficial; formation of PrPSc ceased. However, in uninfected cells EGCG interfered with the stress-protective activity of PrPC. As a consequence, EGCG-treated cells showed enhanced vulnerability to stress conditions. Our study emphasizes the important role of PrPC to protect cells from stress and indicate efficient intracellular pathways to degrade non-native conformations of PrPC.