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This growing challenge necessitates a strategic rethinking of pathogen control, prompting the integration of next-generation therapeutics capable of disrupting Salmonella pathogenesis through novel, antibiotic-sparing mechanisms. In this context, a diverse array of emerging alternatives, including bacteriophages, antimicrobial peptides, probiotics, prebiotics, short-chain fatty acids, nanoparticles, and host-directed immunomodulators, have gained prominence as a promising frontier in non-antibiotic therapeutics. These modalities offer targeted approaches to inhibit Salmonella colonization, virulence expression, and persistence, while minimizing collateral damage to the microbiota and avoiding the propagation of resistance genes. As Salmonella continues to pose a global threat to animal and public health, the development of scalable, resistance-conscious interventions remains a critical priority. Ongoing research efforts are increasingly focused on optimizing delivery systems, dosage strategies, and synergistic combinations to enhance the clinical and field applicability of these alternatives. By harnessing these innovative modalities, the future of Salmonella control may shift toward precision therapeutics that align with One Health principles and sustainable food safety goals.<\/jats:p>","DOI":"10.3390\/antibiotics14101054","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:17:35Z","timestamp":1761056255000},"page":"1054","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Antibiotic Alternatives and Next-Generation Therapeutics for Salmonella Control: A One Health Approach to Combating Antimicrobial Resistance"],"prefix":"10.3390","volume":"14","author":[{"given":"Mohamed","family":"Saleh","sequence":"first","affiliation":[{"name":"Department of Veterinary Science, Martin-Gatton College of Agriculture, Food, and Environment, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashutosh","family":"Verma","sequence":"additional","affiliation":[{"name":"Richard A. Gillespie College of Veterinary Medicine, Lincoln Memorial University, Harrogate, TN 37752, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7638-4942","authenticated-orcid":false,"given":"Khaled A.","family":"Shaaban","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-5418","authenticated-orcid":false,"given":"Yosra A.","family":"Helmy","sequence":"additional","affiliation":[{"name":"Department of Veterinary Science, Martin-Gatton College of Agriculture, Food, and Environment, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Helmy, Y.A., El-Adawy, H., Sanad, Y.M., and Ghanem, M. 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