Critical congenital heart defects (CCHDs) are serious malformations that remain to be an important cause of neonatal mortality and morbidity. The clinical presentations of CCHD are shock, cyanosis, or respiratory distress, which may be similar to that of other neonatal conditions. Failure to diagnose these conditions early on after birth may result in acute cardiovascular collapse and death. Screening with routine pulse oximetry is efficient in distinguishing newborns with CCHD and other hypoxemic illnesses, which may otherwise be potentially life-threatening. If the cardiovascular system cannot be observed by echocardiography, then treatment with continuous prostaglandin-E1(PGE1) infusion should be started in any newborn whose condition deteriorates in the first few days of life. This review aims to provide a concise summary of the presentation and management of various CCHDs and to emphasize the role of timely diagnosis in the management.