Piezoelectric two-dimensional (2D) van der Waals (vdWs) materials are highly desirable for applications in miniaturized and flexible/wearable devices. However, the reverse-polarization between adjacent layers in current 2D layered materials results in decreasing their in-plane piezoelectric coefficients with layer number, which limits their practical applications. Here, we report a class of 2D layered materials with an identical orientation of in-plane polarization. Their piezoelectric coefficients (e22) increase with layer number, thereby allowing for the fabrication of flexible piezotronic devices with large piezoelectric responsivity and excellent mechanical durability. The piezoelectric outputs can reach up to 0.363 V for a 7-layer α-In2Se3 device, with a current responsivity of 598.1 pA for 1% strain, which is 1 order of magnitude higher than the values of the reported 2D piezoelectrics. The self-powered piezoelectric sensors made of these newly developed 2D layered materials have been successfully used for real-time health monitoring, proving their suitability for the fabrication of flexible piezotronic devices due to their large piezoelectric responses and excellent mechanical durability.