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Introduction: We present a robust and up-to-date synthesis of evidence on the effectiveness of interventions to prevent and treat newborn infections in low- and middle-income countries (LMICs). Newborn infection prevention interventions included strategies to reduce antimicrobial resistance (AMR), prevention of healthcare-associated infections (HAIs), clean birth kits (CBKs), chlorhexidine cleansing, topical emollients, and probiotic and synbiotic supplementation. Interventions to treat suspected neonatal infections included prophylactic systemic antifungal agents and community-based antibiotic delivery for possible serious bacterial infections (PSBIs). Methods: A descriptive review combining different methodological approaches was conducted. To provide the most suitable recommendations for real-world implementation, our analyses considered the impact of these interventions within three distinct health settings: facility, mixed, and community. Results: In facility settings, the strongest evidence supported the implementation of multimodal stewardship interventions for AMR reduction and device-associated infection prevention bundles for HAI prevention. Emollients in preterm newborns reduced the risk of invasive infection compared to routine skin care. Probiotics in preterm newborns reduced neonatal mortality, invasive infection, and necrotizing enterocolitis (NEC) risks compared to standard care or placebo. There was insufficient evidence for synbiotics and prophylactic systemic antifungals in LMICs. In mixed settings, CBKs reduced neonatal mortality risk compared to standard care. In community settings, chlorhexidine umbilical cord cleansing reduced omphalitis risk compared to dry cord care. For the treatment of PSBIs, purely domiciliary-based antibiotic delivery reduced the risk of all-cause neonatal mortality when compared to the standard hospital referral. Conclusion: Strategies for preventing HAIs and reducing AMR in healthcare facilities should be multimodal, and strategy selection should consider the feasibility of integration within existing newborn care programs. Probiotics are effective for facility-based use in preterm newborns; however, the establishment of high-quality, cost-effective mass production of standardized formulations is needed. Chlorhexidine cord cleansing is effective in community settings to prevent omphalitis in contexts where unhygienic cord applications are prevalent. Community-based antibiotic delivery of simplified regimens for PSBIs is a safe alternative when hospital-based care in LMICs is not possible or is declined by parents. More randomized trial evidence is needed to establish the effectiveness of CBKs, emollients, synbiotics, and prophylactic systemic antifungals in LMICs. [ABSTRACT FROM AUTHOR]