Reducing background signal and improving detection sensitivity is one of the main research directions of optical biosensors. Based on the structure and functional characteristics of MOFs, the optical sensing system is constructed, which does not require the pre-treatment of complex biological samples or the catalysis of biological enzymes, and can be directly used for the detection of HER2 in serum. In this paper, the fluorescence resonance energy transfer effect between Co/Fe-MOFs and HER2 Aptamer modified fluorescent group FAM was used to make FAM-Apt undergo fluorescence quenching. When the target is present, FAM-Apt specifically binds to HER2 and simultaneously disconnects from Co/Fe-MOFs surface. FAM was recovered, and a reproducible fluorescence sensing system was successfully constructed for the detection of HER2 in serum. The two-dimensional nanosheets and bimetallic structures of Co/Fe-MOFs have greater specific surface area and fluorescence quenching ability. The results showed that the sensor system had good reproducibility (RSD=2.4%), and the detection range of HER2 was 0.01–10 ng/mL under the best conditions, and the estimated detection limit was 6.67 pg/mL.