Aim: To explore the effective clinical screening method and risk factors of congenital heart disease (CHD) in neonates. Materials and Methods: The authors screened neonatal congenital heart diseases using eight clinical screening indexes and analyzed to acquire the simplest and most effective screening method. They also conducted a hospital-based 1:1 matched case (total 64 cases) – control study to analyze a series of underlying risk factors. Result: The eight clinical indexes are reliable screening means. The main risk factors influencing the incidence of CHD in the present samples were abnormal reproductive history (p = 0.008), negative stimulus (p = 0.075), upper respiratory infection (p = 0.06), diabetes mellitus (p = 0.058), high blood pressure (p = 0.041), husband's cigarette smoking (p = 0.001), and gravidity (p = 0.000). Conclusion: The eight clinical indexes were reliable means to screen CHD in neonates. Eliminating abortion or other abnormal reproduction, augmenting maternal mental healthcare, preventing upper respiratory tract infections, limiting medication during early pregnancy including antihypertensive agent, controlling blood glucose levels, and abstaining from cigarette may lower the occurrence of CHD.