Newborns with significant neonatal jaundice (SNJ) would admit for evaluation and/or intervention due to an earlier or more rapid increase in bilirubin level. Bilirubin-induced neurological dysfunction in this population might be underestimated. We aimed to investigate the risk of long-term neurodevelopmental sequelae of SNJ in Taiwan. An SNJ 2000-2003 follow-up cohort consisting of 66,983 neonates was extracted from the nationwide, population-based health insurance database in Taiwan to survey the accumulative incidence of long-term (7-year) neurodevelopmental sequelae in comparison to a reference general-population neonate cohort of 12,579 individuals born in 2000. The SNJ follow-up cohort was furtherly categorized into subgroups according to interventions (phototherapy, intensive phototherapy, and exchange transfusion). The SNJ follow-up cohort exhibited significantly higher cumulative rates of long-term neurodevelopmental sequelae than did the reference cohort (P < 0.05). The risks of infantile cerebral palsy, hearing loss, and developmental delay in the SNJ follow-up cohort were between twice and three times of those in the reference cohort after adjusting for gender, comorbid perinatal disorders and urbanization levels. All intervention subgroups demonstrated higher risks for long-term neurodevelopmental sequelae than the reference cohort (P < 0.05) after adjustment. Patients with SNJ are at risk of developing neurodevelopmental disorders during their growth period. A scheduled follow-up protocol of physical and neurodevelopmental assessment during early childhood for these SNJ patients would potentially be helpful for the early detection of and intervention for neurodevelopmental disorders.