Three-dimensional molecularly imprinted polymers (MIPs) based on quantum dots-grafted covalent organic frameworks (QDs-grafted COFs) are reported in this study. The compound 1,3,5-triformylphloroglucinol-P-phenylenediamine was used as COF material to react with the amino-modified CdSe/ZnS QDs by Schiff-base reactions. The amino-derived QDs reacted with quinoxaline-2-carboxylicacid (QCA) via a non-covalent interaction. The system combines the advantages of MIPs, COFs, and QDs for highly sensitive and selective QCA detection. The MIPs based on QDs-grafted COFs showed good chemical selectivity and thermal stability, as well as consistency in QCA optosensing. Under optimal conditions, the detection limit for QCA in meat and feed samples was 0.85 μmol L−1, over a linear concentration range of 1–50 μmol L−1. The current findings suggest a potential application of MIPs based on QDs-grafted COFs for the detection of trace levels of hazardous chemicals for food safety and environmental control.