Introduction: Retinopathy of Prematurity (ROP) is a vasoproliferative disorder and a leading cause of preventable childhood blindness in premature infants. Its multifactorial pathogenesis has led to numerous preventive strategies, but conflicting evidence often hinders clinical application. This systematic review synthesizes current evidence on the efficacy and safety of various interventions to provide clear guidance for clinical practice. Methods: This systematic review was conducted following PRISMA 2020 guidelines. A comprehensive search was performed across PubMed, Google Scholar, Semantic Scholar, and Springer for studies on ROP prevention in premature neonates. Eligibility screening focused on primary research and systematic reviews examining preventive interventions. After screening 354 records and assessing 201 for eligibility, 23 studies were included for data synthesis and analysis. Results: Significant findings indicate that nutritional interventions are highly effective. Human milk intake was consistently associated with a reduced risk of both any and severe ROP. Enteral supplementation with arachidonic acid/docosahexaenoic acid significantly reduced severe ROP. Evidence for pharmacological agents was mixed; propranolol reduced ROP progression but with notable safety concerns like bradycardia and hypotension , while Vitamin A showed conflicting results across studies. Several agents, including erythropoietin and inositol, were found to be ineffective. Promising newer strategies include biphasic oxygen protocols and cord blood transfusions, which may reduce severe ROP with improved safety. Discussion: The findings underscore the necessity of a multimodal approach to ROP prevention, as no single intervention is a panacea. Foundational strategies like human milk feeding show consistent benefits, whereas many pharmacological agents have conflicting results or significant safety concerns that temper their clinical use. Conclusion: The prevention of ROP requires a tailored, evidence-based strategy prioritizing safe, foundational care like nutritional support. Targeted therapies such as propranolol and novel approaches like cord blood transfusions demand careful consideration of an infant's risk profile and available resources, balancing potential benefits against known risks.