<p>Early recognition of pediatric sepsis remains challenging due to the limited diagnostic performance of conventional biomarkers. This study aimed to evaluate the kinetic profiles of pentraxin-3 (PTX3) and presepsin and their associations with the Phoenix Sepsis Score (PSS) and hemodynamic support requirements. In this prospective single-center study, 40 children with suspected sepsis and 66 healthy controls were enrolled. Patients were classified according to the Phoenix Sepsis Score (PSS) as infection (PSS &lt; 2), sepsis (PSS ≥ 2), and septic shock. Serum PTX3, presepsin, C-reactive protein (CRP), and procalcitonin (PCT) levels were measured at admission and at 48&#xa0;h, and their temporal patterns and clinical correlations were analyzed. Baseline PTX3 levels were significantly higher in septic children than controls (p &lt; 0.001), whereas presepsin showed no difference (p = 0.513). PTX3 varied across clinical severity groups (p &lt; 0.001), while CRP and PCT did not. PTX3 showed high diagnostic accuracy (AUC: 0.872; 95% CI: 0.787–0.958), whereas presepsin performed poorly (AUC: 0.578). Admission PTX3 correlated with vasopressor requirement (r = 0.548, p = 0.042). At 48&#xa0;h, PTX3 decreased significantly (p &lt; 0.001), while presepsin increased (p = 0.034).</p><p><i>Conclusion</i>: Our results suggest that PTX3 may provide added diagnostic utility compared with presepsin for early detection and severity assessment of pediatric sepsis. Its pronounced variation across clinical categories and strong correlation with hemodynamic support indicate that PTX3 could serve as a dynamic biomarker of vascular endothelial activation and subsequent stabilization.<Table Float="No" ID="Taba"> <tgroup cols="1"> <colspec align="left" colname="c1" colnum="1" /> <tbody> <row> <entry align="left" colname="c1"> <p><b>What is Known:</b></p> </entry> </row> <row> <entry align="left" colname="c1"> <p>• <i>PTX3 and presepsin have been proposed as emerging biomarkers for sepsis, however evidence in pediatric populations remains limited</i></p> <p>• <i>Existing pediatric studies report heterogeneous diagnostic performance for presepsin, and data on early kinetic behavior of PTX3 are scarce</i></p> </entry> </row> <row> <entry align="left" colname="c1"> <p><b>What is New:</b></p> </entry> </row> <row> <entry align="left" colname="c1"> <p>• <i>This study demonstrates distinct temporal biomarker dynamics: PTX3 levels decline rapidly with clinical stabilization, whereas presepsin shows a significant late-phase increase within 48&#xa0;h</i></p> <p>• <i>When validated against the Phoenix Sepsis Score, PTX3 exhibits higher diagnostic reliability and a stronger correlation with vasopressor requirements than presepsin, suggesting that it may serve as a more specific indicator of vascular endothelial stress</i></p> </entry> </row> </tbody> </tgroup> </Table></p>