Given the great importance of natural biopreservatives in the modern food industry, lactic acid bacteria (LAB)‐producing bacteriocins have gained considerable attention due to their antimicrobial activity against foodborne pathogens and spoilage bacteria. Although numerous LAB‐producing bacteriocins have demonstrated efficiency in preserving food quality in various applications, only a limited number of these compounds have been commercially approved to date. The currently unclear gastrointestinal metabolism of bacteriocins may pose safety risks, as well as cytotoxicity and immunogenicity, which need to be seriously considered before their application. A more noteworthy concern lies in whether bacteriocins induce an imbalance in the gut microbiota, thereby leading to alterations in the abundance of health‐associated microorganisms and their metabolites in the gastrointestinal tract. Accordingly, this review presents unique insights into the challenges arising from metabolic interactions between LAB‐producing bacteriocins and the gastrointestinal tract. Besides, the application of bacteriocins in the food industry faces challenges arising from the low production yield, weak stability, and insufficient antimicrobial activity. The corresponding development strategies are proposed for conducting the systematic and comprehensive evaluation of the potential safety risks of bacteriocins and their metabolites. The strategies also focus on the rational design to increase the activity and stability, the fermentation control to enhance the production yield, and the hurdle and embedding technology to improve the application effects. It definitively discloses the perspective of bacteriocins to become natural, sustainable, safe, and eco‐friendly biological preservatives for the advancement of the food industry.