Introduction Costello syndrome (CS) is a rare disorder that affects multiple organ systems, which is usually diagnosed postnatally, except for 2 cases diagnosed prenatally from chromosome analysis by amniocentesis. We present the first case of prenatally diagnosed CS via maternal blood testing. Case Description A 38-year-old woman was referred for genetic screening at 28 weeks of gestational age (GA) due to polyhydramnios and shortened limbs seen on prenatal ultrasound. Cell-free DNA, noninvasive prenatal single gene screening was positive for G12S HRAS mutation, which is indicative of CS. The infant was delivered via elective repeat cesarean section at 36 weeks and 6 days GA, was admitted to the neonatal intensive care unit for respiratory distress. Physical examination was significant for macrocephaly, wide depressed nasal bridge, short neck, rhizomelic limb shortening, micropenis, and bilateral equinovarus deformity of the feet. Echocardiography on the first day showed severe pulmonary hypertension. Brain MRI showed a possible cavernous mass lesion and small arachnoid cyst over the left cerebellar hemisphere. Postnatal gene-targeted testing confirmed CS diagnosis with pathogenic variants. The infant was managed for respiratory distress, hypoglycemia, jaundice, and feet deformities. He was subsequently transferred to another hospital at 45 weeks of age for gastrostomy tube placement due to persistent difficulty with oral feeding. Discussion CS affects multiple organ systems. Clinical presentations includes short stature; macrocephaly; coarse facial features, loose and soft skin; hypotonia and joint laxity; cardiac involvement with congenital heart defect, feeding difficulty, and developmental delay. The phenotypic spectrum is wide and can range from mild features to early lethal complications mostly as a result of severe progressive Hypertrophic Cardiomyopathy (HCM) and respiratory compromise. CS is an autosomal dominant genetic disorder caused by mutations in the HRAS gene, but almost all cases have new mutations with no family history. Disease course depends on cardiac and predisposition to benign and malignant tumor complications. Treatment requires a multidisciplinary team directed toward the specific clinical findings. Conclusion To our knowledge, this is the first reported case of prenatally diagnosed CS via maternal blood testing. Molecular diagnosis in the prenatal period allows neonatal care providers to prepare for potential complications in the postnatal period.