Background: Systemic inflammation following cardiopulmonary bypass (CPB) can interfere with analysis of routine clinical and biochemical parameters. Procalcitonin (PCT) is a potential biomarker for diagnosing early postoperative sepsis in pediatric patients following cardiac surgery utilizing CPB. This study aimed to evaluate the diagnostic accuracy of PCT compared to other biomarkers, especially C-reactive protein (CRP), in this clinical setting. Methods: A prospective single-center study was conducted over a 10-month period during the coronavirus disease 2019 (COVID-19) pandemic (2021–2022), enrolling 89 pediatric patients postcardiac surgery. PCT, CRP, and complete blood count were analyzed, and area under the curve (AUC) was employed for statistical analysis. Results: PCT and CRP demonstrated moderate discriminatory ability with AUCs of 0.678 and 0.635, respectively. White cell count exhibited fair discriminatory power, and platelet count performed poorly in distinguishing septic from nonseptic cases (AUC: white cell count, 0.545; platelet, 0.486). Conclusions PCT and CRP hold promise as diagnostic markers for early postoperative sepsis in pediatric cardiac surgery patients. However, these biomarkers are not adequate standalone indicators, emphasizing the continued need for clinical judgment supported by multiple diagnostic parameters.