The ability to identify unknown risks is the key to improving the level of food safety. However, the conventional nontargeted screening methods for new contaminant identification and risk assessment remain difficult work. Herein, a toxic-oriented screening platform based on high-expression epidermal growth factor receptor HEK293 cell membrane-coated magnetic nanoparticles (EGFR/MNPs) was first used for the discovery of unknown contaminants from food samples. The EGFR served as a bait to bind the risk compounds, considering that the abnormal activation of EGFR was related to the incidence of numerous chronic inflammatory diseases. The cell membranes were specifically covalently immobilized on magnetic carriers through metabolic glycoengineering and strain-promoted alkyne-azide cycloaddition (SPAAC) to ensure the stability and bioactivity of the EGFR/MNPs. The synthesized EGFR/MNPs possessed an excellent receptor loading amount and were used to screen potential risk substances from thermally processed food. Finally, two compounds, harman and norharman, were rapidly identified. The toxicological experiments confirmed that the screened compounds could promote EGFR phosphorylation and further activate downstream signaling pathways, thereby inducing cellular oxidative damage. The proposed method provided a toxic-oriented method for identifying risk compounds from food samples.