Complementary metal oxide semiconductor (CMOS) image sensors have been increasingly widely used in the field of radiation environments due to their numerous advantages, and their radiation effects have also attracted much attention. Some experimental studies have shown that the saturation output of CMOS image sensors decreases after irradiation, while others have reported that it increases. In this work, the further in-depth research on the inconsistent results is conducted based on the proton irradiation experiments and TCAD simulations, and the degradation mechanism in full well capacity, conversion factor, and saturation output of the 4T pinned photodiode (PPD) CMOS image sensors due to proton cumulative radiation effects are also analyzed. In experiments, the sensors are irradiated by 12 MeV and 60 MeV protons with a fluence up to 2× 10¹² cm^–2. The sensors are unbiased during irradiation. The experimental results show that proton irradiation at 12 MeV and 60 MeV result in an increase of 8.2% and 7.3% in conversion factor, respectively, and a decrease of 7.3% and 3.8% in full well capacity, respectively. The saturation output shows no significant change trend under 12 MeV proton irradiation, but increases by 3% under 60 MeV proton irradiation. In the TCAD simulation, a three-dimensional 4T PPD pixel model is constructed. A simulation method that combines the trap and gamma radiation model in TCAD with the mathematical model of minority carrier lifetime is used to simulate global and local cumulative proton irradiation in order to analyze the degradation mechanism. It is proposed that the degradation of saturation output at the pixel level is determined by the full well capacity of PPD, the physical characteristics of the reset transistor and the capacitance of floating diffusion, but they have opposite effects. Proton irradiation leads to the accumulation of oxide-trapped positive charges in the shallow trench isolation on both sides of PPD, resulting in the formation of leakage current path in silicon, thereby reducing the full well capacity. A decrease in full well capacity leads to a decrease in saturation output. While, the radiation effect of the reset transistor causes the potential of floating diffusion (FD) to increase during the FD reset phase, further leading to an increase in saturation output. The irradiation causes the capacitance of the floating diffusion to decrease, resulting in an increase in conversion factor and consequently increasing the saturation output. The difference in radiation sensitivity among the three influence factors at the pixel level may result in a decrease or increase in saturation output with proton fluence increasing. The above work comprehensively reveals and analyzes the mechanisms of degradation in full well capacity, conversion factor and saturation output after irradiation, and the research results have certain guiding significance for analyzing the radiation damage to CMOS image sensors.