This manuscript reviews the evolution of newborn screening for primary congenital hypothyroidism (CH) and explores future strategies to enhance diagnostic accuracy. Over the past few decades, newborn screening has expanded globally, significantly reducing the incidence of severe forms of the disease. However, challenges persist, especially regarding the overdiagnosis of mild cases of primary CH, which may not require treatment. Omic sciences may help researchers to enhance the understanding of primary CH and to uncover new biomarkers to identify mild cases with altered proteomic and/or metabolic profiles associated with the need for treatment. Record-linkage studies can help deepen knowledge on the long-term outcomes of affected children identified through newborn screening. Nevertheless, despite 50 years of newborn screening for primary CH, a minority of newborns currently benefit from this critically important public health intervention. Efforts should be done to expand access to newborn screening globally, especially for those born in developing countries.