A study was conducted on the influence of incident pulse laser energy density on the thermal stress at the photosensitive layer (silicon dioxide layer/silicon layer interface) of a nanosecond pulse laser irradiated complementary metal oxide semiconductor (CMOS) photodetector. A simulation geometric structure model of CMOS photodetector was established. Based on the Fourier thermal conduction equation and thermal coupling equation system, the temperature rise and thermal stress at the central point of the photosensitive surface of CMOS photodetector under nanosecond pulse laser irradiation were simulated and calculated. The influences of incident pulse laser energy density on the temperature rise time evolution process and the spatial distribution of thermal stress were discussed. The simulation results show that as the energy density of the incident pulse laser increases, the peak temperature and the thermal stress at the photosensitive layer of the CMOS photodetector increase. When a nanosecond pulse laser irradiates a CMOS photodetector, the tensile stress at the photosensitive layer causes mechanical damage to the CMOS photodetector first. As the laser energy density increases, the thermal damage occurs. The research results have certain theoretical support for the study of the damage mechanism and damage effect of nanosecond pulse laser induced CMOS photodetector.