Microbial resistance (AMR) presents a serious hazard to the poultry sector, particularly concerning bacterial infections, as well as Food-borne microorganisms represent significant pathogens that impact food safety and contribute to human illness globally, primarily through the ingestion of food contaminated with these pathogens or their toxins, particularly in poultry products. Environmental contamination with various Salmonella serotypes is common in commercial laying hen farms and is a major concern for the global poultry industry. Understanding the interrelationships between these agents at the molecular level could help elucidate cross-resistance or co-resistance mechanisms, aiding in the design of effective intervention strategies. A total of 20 isolates of S.T. were obtained from poultry layer flocks. Approximately 80% of these isolates exhibited multidrug resistance (MDR). The minimum inhibitory concentration (MIC) was determined using broth microdilution methods. We investigated the synergistic effects of various nanoparticles, including silver nanoparticles (Ag-NPs), zinc oxide nanoparticles (ZnO-NPs), chitosan nanoparticles (CH-NPs), and zeolite nanoparticles (ZE-NPs), on 15 antibiotic-resistant strains of S.T. The antibacterial properties of these nanoparticles, both individually and in combination with selected antibiotics and biocides, were assessed against the tested S.T. isolates. The findings indicated a significant enhancement in antibiotic efficacy when combined with all tested nanoparticles, with the exception of nalidixic acid, where synergy was observed only with ZnO-NPs. The incorporation of nanoparticles with antimicrobial agents may provide a strategy to combat antibiotic resistance and improve their effectiveness. Furthermore, the results demonstrated a significant increase (p < 0.05) in the antibacterial activity of nanoparticles combined with biocides against S. T compared to the use of antibiotics and biocides alone against S.T., attributed to a notable reduction in MIC50. It can be concluded that the application of nanoparticles as efflux pump inhibitors not only aids in restoring the bactericidal effects of existing antibiotics but also diminishes the capacity of microorganisms to develop biofilms.