We systematically study the fatigue failure of the Ag/Poly (3-hexylthiophene-2,5-diyl)(P3HT)/WO3/ITO/PET flexible memristor under variable temperatures, which simulates essential synaptic learning functions. The theoretical calculations and finite element analysis results indicate that the P3HT/WO3 interface plays a key role in device fatigue failure at variable temperatures. As the temperature dropped from 100 to −30 °C, a significant decrease in the loosely adsorbed polymer chains and flattened chains occurs at the P3HT/WO3 interface and thus leads to the deterioration of the P3HT/WO3 interface. The weak P3HT/WO3 interfacial bonding substantially accelerates the crack propagation under low-temperature flexural cycles, which will ultimately cause the device to deteriorate. Our work may provide some useful information for future achievement of flexible memory synapses utilized in cryogenic environments.