Background: In newborns, persistent pulmonary hypertension (PPHN) poses a serious hazard to life. The principal treatment, inhaled nitric oxide, is believed to be unavailable in developing nations, where mortality is predicted to be between 10% and 20% higher. Objectives: This study aimed to assess the effectiveness, safety, and potential adverse reactions of bosentan and sildenafil when used in newborns with PPHN. Patients and Methods: Between July 2021 and August 2022, a double-blind clinical experiment was carried out at Damietta General Hospital's Neonatal Intensive Care Unit. In newborns with PPHN, the effectiveness, safety, and potential adverse reactions of bosentan and sildenafil were assessed. Comparisons were done between the two groups' echocardiographic results, length of oxygen reliance, need for invasive ventilator assistance, duration of medication, and short-term results such as: blood pressure, white blood cell, and haemoglobin counts. Results: Bosentan has comparable PAP-lowering and cardiac output-improving effects to sildenafil. Bosentan had a considerably shorter treatment period than sildenafil (P = 0.003). During 15 and 17 days, the oxygen need time was comparable between the two groups (P = 0.175). Both groups required invasive breathing support, which was equivalent (P = 0.867). The third echocardiographic research results, including pulmonic inadequacies (P = 0.183), tricuspid regurgitations (P = 0.357), and ejection fractions (P = 0.159), were comparable in the bosentan and sildenafil groups, despite pulmonary artery pressure (PAP) and the intensity of tricuspid valve inadequacy being higher before therapies. Conclusion: Neonatal PPHN is successfully treated with bosentan, which decreased it more quickly. Comparing to sildenafil, it is more effective at lowering PAP and lessens the degree of tricuspid valve dysfunction in a shorter period of time.