2D piezoelectric materials that can realize the mutual conversion of mechanical and electrical energy play an important role in nanoelectromechanical devices. As a new generation of ultra-wide band gap semiconductor, the monoclinic β-Ga2O3 has received extensive attention and research. In this paper, the inversion center of 2D β-Ga2O3was broken by a metal atom substitutional doping. The values of out-of-plane (in-plane) piezoelectric coefficient for Cu-doped and Al-doped β-Ga2O3 reach -4.04 (3.95) pm/V and -2.91 (0.37) pm/V, respectively. Although they are both two-dimensional structures, the results are comparable with those of the commonly used bulk piezoelectric materials such as α-quartz (d11 = 2.3 pm/V), AlN (d33 = 5.1 pm/V), and GaN (d33 = 3.1 pm/V). Our research shows a great potential application of doped β-Ga2O3 in micro and nano-electromechanical devices such as sensitive sensors, smart wearables, and micro energy converters.