This paper presents a novel self-powered mechanical sensing based on the vertical piezo-optoelectronic coupling in a 3C-SiC/Si heterojunction. The vertical piezo-optoelectronic coupling refers to the change of photogenerated voltage across the 3C-SiC/Si heterojunction upon application of mechanical stress or strain. The effect is elucidated under different photoexcitation conditions and under varying tensile and compressive strains. Experimental results show that the relationship between the vertical photovoltage and applied strain is highly linear, increasing under the tensile strain while decreasing under the compressive strain. The highest sensitivities to tensile and compressive strains are 0.146 and 0.058 μV/ppm/μW, respectively, which are about 220 and 360 times larger than those of the lateral piezo-optoelectronic coupling reported in literatures. These extremely large changes in vertical photovoltages are explained by the alteration in effective mass, energy band shift, and repopulation of photogenerated holes in out-of-plane, in-plane longitudinal, and in-plane transverse directions when strains are exerted on the heterojunction. The significant enhancement of strain sensitivity will pave the way for development of ultrasensitive and self-powered mechanical sensors based on the proposed vertical piezo-optoelectronic coupling.