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Background Pulse oximetry screening (POS) is acknowledged globally as a noninvasive method to detect critical congenital heart diseases (CCHDs) and respiratory illnesses. However, its value for early diagnosis and treatment remains unrecognized in many hospitals with limited resources around the world. This study aimed to evaluate POS's application in CCHDs, persistent pulmonary hypertension (PPHN), and respiratory distress syndrome (RDS) for early diagnosis and its influence on clinical procedures in rural areas. Methods This prospective observational study included all eligible newborn infants in the regional neonatal unit of a community healthcare center. Their peripheral oxygen saturation was assessed at <24 hours and >24 hours after birth, in the right upper limb and either lower limb. An oxygen saturation of <95% or >3% difference between pre-ductal and post-ductal circulations was considered abnormal. All neonates with abnormal oxygen saturations at >24 hours after birth were subjected to another POS test within two hours of the last test. If the oxygen saturation was still abnormal, it was considered a positive POS test. The POS results were classified as oxygen saturation abnormal (<90%), abnormal (90-94%), and normal (≥95%). All neonates with a positive POS test were referred for echocardiography. Results Overall, 440 infants had documented POS results. A total of 65 (14.77%) infants had a positive POS test result, out of which 39 (8.86%) cases were diagnosed on further evaluation. Four neonates had CCHD (positive predictive value (PPV) = 6.15%), 26 had RDS (PPV = 40%), and nine had PPHN (PPV = 13.85%). Without any further delay, the doctor directed them all to a more advanced facility. Conclusion Our research showed that, in large-scale clinical settings, the addition of pulse oximetry to routine cardiac auscultation could be a reliable and feasible method to screen newborns for CCHD, PPHN, and RDS early on. Our research underscores the importance of implementing routine POS to detect CCHD, RDS, and PPHN in clinical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Gaonkar et al.)