Staphylococcus aureus (S. aureus) is a major foodborne pathogen. Amid escalating antibiotic selection pressure, the prevalence of multidrug-resistant S. aureus strains throughout the food chain has risen continuously, posing grave threats to food safety and public health. Constituting the core regulatory framework mediating antibiotic resistance in foodborne S. aureus, signaling pathway regulatory systems are highly responsive to the food matrix and processing conditions, rendering them a critical starting pointing for deciphering bacterial resistance mechanism and designing targeted control strategies. This review systematically summarizes the current contamination status and hazard characteristics of foodborne drug-resistant S. aureus, with focus on the key signaling pathways (including quorum sensing and two-component signal transduction systems) and their roles in mediating the development of antibiotic resistance. Finally, it recapitulates signaling pathway-based targeted control strategies for S. aureus in the food chain, aiming to provide theoretical support for the development of targeted control techniques.