The invention belongs to the technical field of biological medicines, and particularly relates to a molecular marker for prenatal noninvasive diagnosis of fetuses with cleft lip and palate, neural tube malformation and congenital heart disease and application of the molecular marker. The molecular marker for prenatal noninvasive diagnosis of the fetuses with cleft lip and palate, neural tube malformation and congenital heart disease comprises three piRNAs including hsa-piR-009228, hsa-piR-016659 and hsa-piR-020496. The invention further discloses application of the molecular marker for prenatal noninvasive diagnosis in preparation of products for prenatal screening, early warning, clinical diagnosis and biochemical examination of the fetuses with cleft lip and palate, neural tube malformation and congenital heart disease. The molecular marker and the application have the advantages that gene expression abnormality of piRNAs in blood of pregnant women is discovered and confirmed for thefirst time to be closely related to occurrence of the fetuses with cleft lip and palate, neural tube malformation and congenital heart disease, verified sample sizes are large, results are accurate,and a novel way is provided for prenatal screening, early warning and diagnosis of the fetuses with cleft lip and palate, neural tube malformation and congenital heart disease.