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Purpose Congenital hyperinsulinism (CHI) is the commonest cause of persistent hypoglycaemia in neonates and infants (blood glucose <3.0 mmol/L in first 2–3 days of life; <3.5 mmol/L after 3 days of life). Diazoxide demonstrates variable efficacy depending on the underlying genetic variant and clinical phenotype. Diazoxide has been associated with side effects that are likely dose dependent. This narrative review synthesizes current evidence on diazoxide’s pharmacokinetics and side effect profile to support the development of individualised dosing strategies guided by genotype and patient-specific risk factors, with the aim of optimizing therapeutic outcomes and minimizing adverse effects. Methodology A structured PubMed search was performed to review diazoxide use in hyperinsulinism (HI). Articles not involving neonatal HI, not specifying diazoxide dosing or focusing on alternative therapies were excluded. Addition articles were identified through reference screening or hand searched. Results Traditional diazoxide dosing (5–15 mg/kg/day) is being challenged by emerging evidence supporting the benefits of lower starting doses (2–5 mg/kg/day), particularly in neonates with transient HI or specific genetic variants such as HNF1A and HNF4A . Lower starting doses in selected CHI patients have been shown to achieve adequate glycaemic control with fewer complications, including pulmonary hypertension (PH) and fluid retention. Diazoxide-responsiveness correlates strongly with the underlying molecular etiology. ABCC8 and KCNJ11 gene mutations often predict diazoxide-unresponsiveness, whereas GLUD1 , HADH , and other variants typically predict responsiveness. Early predictors of unresponsiveness include large for gestational age (LGA) status (unrelated to maternal diabetes), early neonatal onset, and the need for high glucose infusion rates (GIR). Risk factors for adverse effects include renal impairment, prematurity, and low albumin levels, which may increase free diazoxide concentrations and drug toxicity. Conclusion Individualized dosing based on clinical phenotype and genotype can improve safety and effectiveness in CHI management. Lower initial doses are recommended in patients with propensity for diazoxide sensitivity or risk factors for adverse events, while more rapid escalation may be warranted in suspected diazoxide-resistant cases.