Congenital heart disease (CHD) is one of the commonest congenital malformations that are mostly asymptomatic at birth, which challenges the diagnosis of neonatal CHD. An early accurate prenatal diagnosis will give parents a choice, as well as the opportunity to plan the delivery and improve the postnatal outcome. The purpose of the study is to evaluate the value of heart murmurs, SpO2 abnormalities, tachypnea, and extracardiac malformations in screening neonatal CHD. All 4500 newborns in the obstetrics department of our hospital from January 2019 to January 2020 are selected as study subjects. Newborns were grouped according with the presence of heart murmurs, tachypnea, transdermalSpO2<95%,and extracardiac malformations alone or in combination (≥3). Patients with murmur, tachypnea, and abnormal SpO2 were assigned into group A, those with murmur, tachypnea, and extracardiac malformations into group B, those with murmurs, SpO2, and extracardiac malformations into group C, those with SpO2, tachypnea, and extracardiac malformations into group D, and those with all four into group E. The color echocardiography identified 65 children with CHD (1.4%) among the included 4,500 newborns. When murmur, tachypnea, abnormal SpO2, and extracardiac malformation were independently used to diagnose CHD, the sensitivity ranged from 30.68% to 51.26%, with specificity ranging from 47.36% to 82.65% and Youden’s index (YI) ranging from 0.13 to 0.36. When murmur, tachypnea, abnormal SpO2, extracardiac malformation were together used to diagnose CHD, 91.23% sensitivity, 95.26 specificity, and 0.91 YI were observed. In conclusion, a combination of four indicators, murmur, tachypnea, abnormal SpO2, and extracardiac malformation yielded good performance in diagnosing neonatal CHD.