<b><i>Background:</i></b> Exchange transfusion (ET) for severe neonatal hyperbilirubinemia (SNH) is frequently undertaken in low- and middle-income countries (LMIC), in sharp contrast to the prevailing practice in high-income countries. However, the criteria for initiating this procedure in settings with limited resources for treating infants with SNH have not been systematically explored. <b><i>Objective:</i></b> To identify key considerations for initiating ET in resource-poor countries to curtail its unnecessary use for the prevention of kernicterus. <b><i>Methods:</i></b> A review of the existing guidelines and literature on the management of neonatal hyperbilirubinemia worldwide was conducted to identify criteria and underlying factors for initiating ET. <b><i>Results:</i></b> There is a dearth of evidence from randomized clinical trials to support clear criteria for indicated ET worldwide. Because risk assessment for kernicterus based solely on the levels of total serum bilirubin (TSB) has often proved inadequate, a combination of plasma/serum bilirubin estimation and clinical evaluation for acute bilirubin encephalopathy (ABE) has been recommended for predicting the risk of kernicterus. However, there is a lack of consistency regarding the TSB levels for which ET should be initiated in relation to the clinical signs/symptoms of ABE and hemolytic disorders. <b><i>Conclusions:</i></b> A decision-making framework that combines TSB thresholds and evidence of neurotoxicity is needed for evaluating the risk of kernicterus and prioritising infants for ET in LMICs to curtail unnecessary interventions.