Newborn screening (NBS) of inborn errors of metabolism (IEMs) is based on the reference ranges established on a healthy newborn population using quantile statistics of molar concentrations of biomarkers and their ratios. The aim of this paper is to investigate whether multivariate independent component analysis (ICA) is a useful tool for the analysis of NBS data, and also to address the structure of the calculated ICA scores. NBS data were obtained from a routine NBS program performed between 2013 and 2022. ICA was tested on 10,213/150 free-diseased controls and 77/20 patients (9/3 different IEMs) in the discovery/validation phases, respectively. The same model computed during the discovery phase was used in the validation phase to confirm its validity. The plots of ICA scores were constructed, and the results were evaluated based on 5sd levels. Patient samples from 7/3 different diseases were clearly identified as 5sd-outlying from control groups in both phases of the study. Two IEMs containing only one patient each were separated at the 3sd level in the discovery phase. Moreover, in one latent variable, the effect of neonatal birth weight was evident. The results strongly suggest that ICA, together with an interpretation derived from values of the “average member of the score structure”, is generally applicable and has the potential to be included in the decision process in the NBS program.