Taking the zeolitic imidazolate framework (ZIF-67) as the precursor, p-type semiconducting CoO-Au polyhedra were synthesized and used as the signal amplifier to construct a sensitive photoelectrochemical (PEC) sensor for caspase-3 activity assay. Here, the n-type semiconductor BiS-modified indium-tin oxide (ITO) slice was used as the photoelectrode. After immobilization of the biotin-DEVD-peptide (biotin-Gly-Asp-Gly-Asp-Glu-Val-Asp-Cys) onto the BiS surface, the streptavidin-labeled CoO-Au polyhedra were introduced to the sensing platform via the specific interaction between biotin and streptavidin. The CoO-Au polyhedra can not only quench the photocurrent of the BiS because of the competitive consumption of electron donors and exciting light energy (p-n-type semiconductor quenching effect), but also act as peroxidase mimetics to produce catalytic precipitate. Additionally, the steric hindrance effect from the CoO-Au polyhedra will decrease the PEC response of the BiS. Ingeniously, the precipitates can not only deposit on the ITO electrode to decrease the photocurrent of PEC sensor, but also act as electron acceptors to scavenge the photogenerated electrons of CoO-Au polyhedra, leading to enhanced quenching ability of the CoO-Au polyhedra. When caspase-3 exists, caspase-3 can specifically recognize and cleave the biotin-DEVD-peptide, resulting in the increase of PEC response. Based on the multifunctional CoO-Au polyhedra, caspase-3 is detected sensitively with a linear range from 0.5 to 50 ng mL and limit of detection down to 0.10 ng mL. The CoO-Au polyhedra provide a novel signal amplifier to construct PEC sensing platform and may have potential applications in bioanalysis, disease diagnostics, and clinical biomedicine.