Background: Sepsis is a common and serious complication in pediatric hematology oncology (PHO) patients. The Endothelial Activation and Stress Index (EASIX) score offers a potentially accessible tool for risk stratification in septic patients. Our objective was to evaluate the association of the EASIX score with adverse clinical outcomes among septic PHO patients. Methods: A retrospective review was conducted for all PHO patients admitted to the intensive care unit (ICU) with sepsis from July 2022 to December 2024. Results: A total of 53 patients with 65 sepsis events were included in this analysis. The median age was 14.9 [IQR 9.9] y and the most common disease was hematologic malignancy. In our cohort, 60% needed vasopressors, 36% required invasive mechanical ventilation, and 22% underwent renal replacement therapy (RRT). Log2-EASIX > 2.5 was associated with higher vasopressor requirements (87% versus 45% in the low log2-EASIX group, p = 0.001) and an increased need for RRT (39% versus 12%, p = 0.024). Septic PHO patients with log2-EASIX > 2.5 were 6.9 times more likely to require vasopressor support [(95% CI 1.7–27.8) p = 0.007]. In addition, PHO patients with log2-EASIX > 2.5 had a longer ICU stay (7 d versus 2 d in the low log2-EASIX group, p = 0.024) and an extended overall hospitalization (33 d versus 25 d, p = 0.029). Conclusions: A higher EASIX score was associated with adverse outcomes in critically ill septic PHO patients. Our findings suggest that the EASIX score can be used as a tool for identifying septic patients at an increased risk of clinical deterioration and poor outcomes. Prospective studies in larger cohorts are warranted to validate and expand upon these findings.