Objective To explore the differential diagnosis of hydrops fetalis and the rare presentations of neonatal congenital hypothyroidism. Methods The data of one congenital hypothyroidism diagnosed neonate with hydrops fetalis leading to birth asphyxia and respiratory failure were retrospectively analyzed. The relevant literatures were reviewed. Results A Uyghur female infant by cesarean delivery at gestational age of 38+5 week for intrauterine distress, presented general edema with cyanosis and dyspnea after birth. Trachea cannula was used to assist ventilation. At one-day old, the thyroid function examination showed that the serum thyroid stimulating hormone was >100 mU/L and the free thyroid was 6.56 pmol/L. Moreover, ultrasonographic examination indicated the thyroid aplasia. The clinical symptoms were improved after the treatment with the levothyroxine tablets replacement, and breathing machine was removed at 8-day old. The dosage of drug was adjusted by clinical manifestation and laboratory monitoring. The patient was discharged at 18-day old with the medicine and was followedup. Conclusions Congenital hypothyroidism can be the pathogenesis of hydrops fetalis and its differential diagnosis should be paid attention.