Introduction: Congenital heart diseases (CHDs) are common congenital anomalies, which if left untreated account for higher mortality and morbidity. Early detection and surgical correction of CHDs are the best treatment measures. The current study aims to test whether Masimo signal extraction technique (SET) pulse-oximeter, which uses signal extraction technology improves the detection rate of CHDs with its overall sensitivity, specificity, and accuracy. Subjects and Methods: The current prospective, observational study was conducted at a tertiary medical center over a period of 2 years. All the neonates' pre- and post-ductal oxygen saturation along with clinical examination was performed within 24 h of life. Postductal reading of ≤ 95% and/or with difference between pre- and postductal of > 5% was considered to be positive for CHDs. Infants with clinical symptoms or test positive for pulse oximetry were referred for echocardiographic confirmation. Results: A total of 2213 infants were observed. Seventeen CHD cases were detected during the study period. Four hundred and fifteen infants tested positive with the pulse oximeter. Ten of them had minor or major CHD and two of the infants had critical CHD. The overall sensitivity of pulse oximetry screening was 70.59% (95% CI), specificity of 81.65%, and a diagnostic accuracy of 81% for any CHDs. Conclusion: Masimo SET pulse oximeter is a sensitive tool for detecting CHDs. A pulse oximeter in combination with clinical examination aids in the better detection rate of CHD. Echocardiography must be considered in all infants who test positive with pulse oximeter or any abnormal findings in the clinical examination.