<p>Neonatal sepsis continues to pose rising critical challenges to global health, particularly in low and middle-income countries, where it accounts for a substantial proportion of neonatal morbidity and mortality. The increasing prevalence of multidrug-resistant (MDR) pathogens in neonatal sepsis has significantly weakened the efficacy of conventional antibiotics, necessitating urgent exploration of alternative antimicrobial therapies for better clinical outcomes. Emerging research interest is growing to develop the microbial-derived peptides as novel antimicrobial agents, particularly “bacteriocins.” In comparison to traditional antibiotics, many bacteriocins exhibit narrow-spectrum action, enabling them to inhibit specific pathogens without disrupting the host microbiota. Recent studies have highlighted the remarkable potential of lactic acid bacteria (LAB) derived bacteriocins in combating MDR pathogens responsible for neonatal sepsis. In this review, we compile current literature on the in vitro antimicrobial activity of LAB-derived bacteriocins, molecular diversity, mechanisms of action and clinical potential. Special attention is given to bacteriocins produced by LAB associated with the milk-derived microbiota, whose natural protective functions could be particularly beneficial for immunocompromised newborns. Additionally, we discuss the physicochemical properties of microbial peptides, including thermal stability, enzymatic resistance, and pH tolerance, which support their suitability for pharmaceutical applications. Overall, LAB-derived bacteriocins represent a novel, biocompatible, and complementary antimicrobial strategy integrated with conventional antibiotics to fight against MDR in neonatal sepsis. Further research and multicentric clinical trials are necessary to fully explore its compliance and efficacy as a future antimicrobial agent in neonatal medicine to underscore their potential as adjunct or preventive biotherapeutics in NICU settings.</p>