The risk of mortality and morbidity of patients with congenital heart defects (CHDs) is highest during neonatal period and increases when diagnosis and proper management are delayed. Neonates with critical CHDs may present with severe cyanosis, respiratory distress, shock, or collapse, all of which are also frequent clinical presentations of various respiratory problems or sepsis in the newborn. Early diagnosis and stabilization and timely referral to a tertiary cardiac center are crucial to improve the outcomes in neonates with CHDs. In this review, the clinical presentation of critical and potentially life-threatening CHDs is discussed along with brief case reviews to help understand the hemodynamics of these defects and ensure proper decision-making in critically ill patients.