Vitamin K prophylaxis represents a paradigmatic example of how molecular mechanisms directly translate into effective neonatal preventive care. In newborns, physiological immaturity of vitamin K metabolism, including limited placental transfer, low hepatic reserves, immature intestinal absorption, and dependence on vitamin K-dependent γ-carboxylation pathways, creates a unique vulnerability to vitamin K deficiency bleeding (VKDB). This narrative review integrates molecular and biochemical mechanisms with neonatal physiology and clinical evidence to examine the effectiveness of current prophylactic strategies. At the molecular and pharmacokinetic level, intramuscular (IM) administration ensures sustained bioavailability and reliable activation of vitamin K-dependent proteins, whereas oral regimens are more sensitive to formulation, dosing schedules, and absorption efficiency. Consistently, clinical and surveillance data demonstrate near-complete protection against both classic and late VKDB following IM prophylaxis, while oral approaches show greater variability, particularly in real-world settings. Importantly, increasing parental refusal of IM vitamin K undermines an intervention with well-established molecular efficacy, contributing to preventable severe bleeding events. By linking mechanistic foundations to clinical outcomes and implementation challenges, this review provides a translational framework for clinicians, researchers, and policymakers aiming to optimize neonatal vitamin K prophylaxis in contemporary practice.