Non-nucleic acid targets have posed a serious challenge to food safety. The detection of non-nucleic acid targets can enable us to monitor food contamination in a timely manner. In recent years, the CRISPR/Cas system has been extensively explored in biosensing. However, there is a lack of a summary of CRISPR/Cas-powered detection tailored to non-nucleic acid targets involved in food safety. This review comprehensively summarizes the recent advances on the construction of CRISPR/Cas-powered detection and the promising applications in the field of food safety related non-nucleic acid targets. The current challenges and futuristic perspectives are also proposed accordingly. The rapidly evolving CRISPR/Cas system has provided a powerful propellant for non-nucleic acid target detection via integration with aptamer and/or DNAzyme. Compared with traditional analytical methods, CRISPR/Cas-powered detection is conceptually novel, essentially eliminates the dependence on large instruments, and also demonstrates the capability for rapid, accurate, sensitive, and on-site testing.