\nIntroduction: This study aimed to develop models for predicting total serum bilirubin by correcting errors of transcutaneous bilirubin using machine learning based on neonatal biomarkers that could affect spectrophotometric measurements of tissue bilirubin. Methods: This retrospective study included infants born at our hospital (≥36 weeks old, ≥2,000 g) between January 2020 and December 2022. Infants without a phototherapy history were included. Robust linear regression, gradient boosting tree, and neural networks were used for machine learning models. A neural network, inspired by the structure of the human brain, was designed comprising three layers: input, intermediate, and output. Results: Totally, 683 infants were included. The mean (minimum-maximum) gestational age, birth weight, participant age, total serum bilirubin, and transcutaneous bilirubin were 39.0 (36.0–42.0) weeks, 3,004 (2,004–4,484) g, 2.8 (1–6) days of age, 8.50 (2.67–18.12) mg/dL, and 7.8 (1.1–18.1) mg/dL, respectively. The neural network model had a root mean square error of 1.03 mg/dL and a mean absolute error of 0.80 mg/dL in cross-validation data. These values were 0.37 mg/dL and 0.28 mg/dL, smaller compared to transcutaneous bilirubin, respectively. The 95% limit of agreement between the neural network estimation and total serum bilirubin was −2.01 to 2.01 mg/dL. Unnecessary blood draws could be reduced by up to 78%. Conclusion: Using machine learning with transcutaneous bilirubin, total serum bilirubin estimation error was reduced by 25%. This integration could increase accuracy, lessen infant discomfort, and simplify procedures, offering a smart alternative to blood draws by accurately estimating phototherapy thresholds. Neonatal jaundice is a common condition that might occur in the first week of life. Severe high bilirubin levels can lead to long-term problems like cerebral palsy, hearing impairment, and developmental delay. Therefore, newborns are usually evaluated for jaundice every day during their first week. To accurately assess jaundice, we need to measure the total bilirubin in the blood. However, daily blood draws for bilirubin measurements can be uncomfortable and may cause anemia in newborns. Thus, transcutaneous bilirubinometry is devised. It is a device that measures bilirubin through the skin and is commonly used because it is non-invasive. However, transcutaneous bilirubinometry has some accuracy issues. In this study, we successfully improved the accuracy of bilirubin measurement by combining machine learning with transcutaneous bilirubinometry. Being used alone, the transcutaneous bilirubinometer had an error of 1.08 mg/dL. However, combining transcutaneous bilirubinometry with machine learning, the error decreased to 0.80 mg/dL, which is a 25% of improvement. Using this approach, unnecessary blood draws could be reduced by up to 78%. If we incorporate this algorithm into transcutaneous bilirubinometry, this novel method has the potential to improve prediction accuracy and reduce the burden on babies. [ABSTRACT FROM AUTHOR]