Here we developed a haplotype-based noninvasive prenatal diagnosis method for hyperphenylalaninemia (HPA) and demonstrated its accuracy and feasibility during early pregnancy. Capture sequencing was performed on genomic DNA from parents and probands using customized hybridization probes targeting highly heterozygous single-nucleotide polymorphisms located within the 1 M region flanking phenylalanine hydroxylase (PAH) and 6-pyruvoyltetrahydropterin (PTS) and its coding region to determine the parental haplotypes and linkage to pathogenic mutations. Maternal plasma DNA obtained at 12-20 weeks of gestation was also subjected to targeted sequencing to deduce the fetal haplotypes based on the parental haplotypes. The fetal genotypes were further validated by invasive prenatal diagnosis. Haplotype-based noninvasive prenatal testing was successfully performed in 13 families. Five fetuses were identified to harbor bi-allelic pathogenic variants of PAH, four fetuses were carriers of one heterozygous PAH variant, three fetuses were normal, and the fetus of the 6-pyruvoyl tetrahydrobiopterin synthase family was identified as normal. The fetal genotypes at two gestational weeks from the same PAH family were identical. All results were consistent with the prenatal diagnosis based on amniotic fluid. Haplotype-based noninvasive prenatal testing for HPA through targeted sequencing is accurate and feasible during early gestation.