The practical implementation of photoelectrochemical devices for hydrogen generation is limited by their short lifetimes. Understanding the factors affecting the stability of the heterogeneous photoelectrodes is required to formulate degradation mitigation strategies. We developed a multiscale and multiphysics model to investigate and quantify the photostability of photoelectrodes. The model considers the photophysical processes in an electrocatalyst-coated semiconductor immersed in electrolyte, and the kinetics of the competing water-splitting and photocorrosion reactions. When applied to 12 promising compound semiconductors for use as photoanodes (GaAs, GaP, InP, GaN, SiC, AlP, AlAs, CdTe, CdS, CdSe, ZnS, and ZnSe), the semiconductor–electrocatalyst interfacial charge transfer rate constant was found to be the most significant parameter for stabilizing the photoelectrodes. Its increase induced a sigmoid-like increase in photostability, and its optimization made it possible to stabilize nine semiconductors. The semiconductor surface back-bond energy also increased the photostability in a sigmoid-like response, and its optimization allowed to stabilize five semiconductors. The increase of irradiance induced a logarithmic drop in photostability, and limiting it to 100 W/m2 could stabilize three semiconductors. We further observed that the photostability in a device of centimeter-scale can vary by more than 50%, showing stable zones and photocorrosion hotspots. The photoelectrode’s length as well as the electrocatalyst and electrolyte conductivities were found to be relevant parameters to impact this heterogeneity in the photostability. Thus, the photostability is not only defined by material properties but also by the specific combination of materials and by the device architecture. The model presented in this study can also be applied to photocathodes and other PEC designs, and can serve as a design tool for understanding, quantifying, and improving the stability.