The development of artificial intelligence and the Internet of things has motivated extensive research on self-powered flexible sensors. The conventional sensor must be powered by a battery device, while innovative self-powered sensors can provide power for the sensing device. Self-powered flexible sensors can have higher mobility, wider distribution, and even wireless operation, while solving the problem of the limited life of the battery so that it can be continuously operated and widely utilized. In recent years, the studies on piezoelectric nanogenerators (PENGs) and triboelectric nanogenerators (TENGs) have mainly concentrated on self-powered flexible sensors. Self-powered flexible sensors based on PENGs and TENGs have been reported as sensing devices in many application fields, such as human health monitoring, environmental monitoring, wearable devices, electronic skin, human–machine interfaces, robots, and intelligent transportation and cities. This review summarizes the development process of the sensor in terms of material design and structural optimization, as well as introduces its frontier applications in related fields. We also look forward to the development prospects and future of self-powered flexible sensors.