Background: The aim of this study was to evaluate the usefulness of C-Reactive Protein (CRP), Procalcitonin (PCT), and Interleukine 6 (IL6) biomarkers in predicting the existence of high-risk episodes (HRE) during the first 24 h of fever in pediatric cancer patients. HRE were defined as the presence of Gram-negative bloodstream infections or Systemic Inflammatory Response Syndrome. Methods: The study included 103 consecutive fever episodes in 44 hemato-oncological pediatric patients, from whom samples for biomarkers were taken upon initial evaluation (CRP-1, PCT-1 and IL6-1) and then between 12 and 24 h afterward (CRP-2, PCT-2 and IL6-2). Results: An IL6-1 value higher than 164 pg/mL showed an area under the curve (AUC) of 0.890 (0.791–0.989) and OR of 48.68 (7.92–951.42, p < 0.001) to detect HRE in multivariate analysis. A PCT-1 higher than 0.32 ng/mL showed an AUC of 0.805 (0.700–0.910) and OR of 4.55 (0.90–27.84, p = 0.076). A PCT-2 higher than 0.94 ng/mL showed an AUC of 0.836 (0.725–0.947) and OR of 13.01 (1.82–149.13, p = 0.018), and an increase in CRP between the first and second sample (CRP-2vs1) higher than 291% also showed an AUC of 0.785 (0.655–0.915) and OR of 31.09 (4.87–355.33, p = 0.001). Conclusions: IL6-1, PCT-2, and CRP-2vs1 showed a strong and independent correlation with HREs in pediatric cancer patients. CRP variations over the first 24 h provide an improvement in predictive models that are especially useful if IL-6 and PCT are not available.