Highly stable piezo-immunoglobulin-biosensing has been realized from a SiO2/ZnO nanowire (NW) nanogenerator (NG) as a self-powered/active biosensor. The piezoelectric output generated by the SiO2/ZnO NW NG can act not only as a power source for driving the device, but also as a sensing signal for detecting immunoglobulin G (IgG). The stability of the device is very high, and the relative standard deviation (RSD) ranges from 1.20% to 4.20%. The limit of detection (LOD) of IgG on the device can reach 5.7 ng mL(-1). The response of the device is in a linear relationship with IgG concentration. The biosensing performance of SiO2/ZnO NWs is much higher than that of bare ZnO NWs. A SiO2 layer uniformly coated on the surface of the ZnO NW acts as the gate insulation layer, which increases mechanical robustness and protects it from the electrical leakages and short circuits. The IgG biomolecules modified on the surface of the SiO2/ZnO NW act as a gate potential, and the field effect can influence the surface electron density of ZnO NWs, which varies the screening effect of free-carriers on the piezoelectric output. The present results demonstrate a feasible approach for a highly stable self-powered/active biosensor.