Background: Children with β-thalassemia major are at risk of early cardiac dysfunction due to chronic anemia and transfusion-related iron overload. NT-proBNP is a widely used biomarker for cardiac stress, yet its clinical correlates in pediatric thalassemia remain insufficiently defined.Objective: To evaluate the relationship between NT-proBNP levels and clinical variables—including hemoglobin, ferritin, transfusion parameters, and nutritional status—in children with β-thalassemia major receiving routine transfusions.Methods: A cross-sectional study was conducted on 68 pediatric patients at Dr. Moewardi General Hospital. NT-proBNP, hemoglobin, ferritin, transfusion history, anthropometrics, and chelation data were collected. Correlation tests, multivariate bootstrapped linear regression, and logistic regression were used to identify clinical predictors of elevated NT-proBNP (≥125 pg/mL).Results: Median NT-proBNP was 161.5 pg/mL, with 63.2% of participants exceeding the 125 pg/mL threshold. NT-proBNP showed a significant negative correlation with hemoglobin (ρ = –0.298; p = 0.014) and a significant positive correlation with transfusion volume per kilogram (ρ = 0.412; p < 0.001). Ferritin, duration of transfusion, nutritional status, age, sex, and chelation dose were not significantly associated. In multivariate analysis, transfusion volume remained a significant predictor of higher NT-proBNP (B = 9.33; p = 0.013), whereas hemoglobin showed a non-significant negative trend (B = –23.52; p = 0.073). Logistic regression showed no significant independent predictors of NT-proBNP elevation.Conclusion: NT-proBNP elevation in pediatric β-thalassemia major is primarily related to anemia severity and transfusion volume rather than iron overload indicators. NT-proBNP may serve as an early marker of cardiac strain, but imaging remains essential to distinguish hemodynamic effects from subclinical cardiomyopathy.