Abstract <p>Serum amyloid A (SAA), an acute-phase inflammatory protein, demonstrates significant association with central nervous system complications (CNSC). This study investigated the predictive value of SAA for CNSC development during induction chemotherapy in pediatric patients with acute leukemia (AL). A&#xa0;retrospective cohort study was conducted involving 96 newly diagnosed AL pediatric patients, stratified into AL without CNSC (<i>n</i> = 64) and AL with CNSC (<i>n</i> = 32) groups. Comparative analysis of clinical characteristics and laboratory parameters was performed. Statistically significant variables (<i>P</i> &lt; 0.05) from univariate analysis (including risk stratification, white blood cell (WBC) count, SAA, and osteopontin [OPN]) were entered into multivariate logistic regression models to identify independent risk factors. Predictive performance was assessed through receiver operating characteristic (ROC) curve analysis, with area under the curve (AUC) calculation. Subgroup analyses utilized predefined cutoff values for SAA and OPN, while Kaplan–Meier survival curves with log-rank tests evaluated clinical outcomes. A restricted cubic spline regression model examined potential nonlinear associations between biomarker levels and CNSC risk. The AL-CNSC group exhibited significantly elevated OPN and SAA levels (both <i>P</i> &lt; 0.01). Multivariate analysis identified both OPN (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.01–1.04; <i>P</i> &lt; 0.01) and SAA (OR = 1.96, 95% CI: 1.28–3.00; <i>P</i> &lt; 0.01) as independent CNSC risk factors, demonstrating strong predictive capacity (AUC &gt; 0.7). CNSC incidence markedly increased when SAA exceeded 10.22 mg/L or OPN surpassed 300.50 pg/mL. Spline regression confirmed dose-dependent linear relationships between both biomarkers and CNSC risk. Elevated SAA and OPN levels correlate with increased CNSC susceptibility in AL pediatric patients, serving as independent prognostic biomarkers with high clinical predictive value.</p>