Flexible functional devices based on two dimensional (2D) materials are extremely suitable for malleable, portable and sustainable applications, such as health monitoring, electronic skin and optoelectronics. In this work, we developed a flexible photodetector based on a p-CuO/n-MoS2 heterojunction with an enhancement in photocurrent and detection sensitivity. Because of the non-centrosymmetric structure in monolayer MoS2, the piezo-potential induced by applied strain adjusts the band structure at the heterojunction interface and broadens the depletion region based on the piezo-phototronic effect. The border depletion can be discreetly used to improve the photo-generated carrier separation and transport to enhance photoresponse performance. When illuminated by a 532 nm laser, the photocurrent of the heterojunction can be enhanced 27 times under a tensile strain of 0.65% compared to strain free conditions and the detection sensitivity can reach up to 3.27 × 108 Jones. As a result, our research provides a new strategy for novel design and performance optimization of 2D material heterostructures in the application of optoelectronics.