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With the increasingly widespread application of CMOS image sensors (CIS) in radiation environments, such as aerospace, their radiation effects have gained attention. This paper investigates single-event transient (SET) caused by the proton direct ionization on CIS, combining both experimental and simulation methods. The proton beam energy used in the experiment is 12 MeV, with a flux up to 3.5 × 108 p/(cm2 s). Due to the periodicity of the proton beam, the CIS output displays a phenomenon of alternating brightness and darkness. When the proton beam flux is low, numerous SET bright spots with different outputs are observed. To comprehensively analyze these experimental phenomena, a typical three-dimensional 4T pinned photodiode model is constructed in TCAD, and relevant SET simulation is carried out. The results indicate that incident position, incident time, and the number of incident protons significantly affect the output of SET-generated bright spots, which are key factors contributing to the different bright spots observed in the experiment.