Background: Blood transfusion can be considered as a life-saving treatment and is a primary health management topic. This study aims to assess the appropriateness of blood transfusion performed in a large tertiary hospital in Italy. Methods: a multispecialist team composed oof hematologists, public health experts and pediatricians analyzed blood transfusions performed between 2018 and 2022 in the pediatric wards comparing the appropriateness with the available NHS guidelines available. Patients’ characteristics, clinical features and blood component’s data were collected and analyzed. Results: considering 147 blood transfusions performed in 2018–2022, only eight (5.4%) were performed according to guidelines, while 98 (66.7%) were driven by clinicians’ expertise, especially for anemia in genetic syndromes (30) (20.5%) and autoimmune diseases (20) (13.6%). Thirty-nine (26.5%) transfusions could be considered as inappropriate, while two (1.4%) blood packs were never been transfused after being requested. Conclusions: This analysis is one of the first performed to assess the appropriateness of blood component transfusions comparing their compliance to NHS guidelines. The importance of this analysis can be explained first by the clinical point of view and second by the economic one.