Purpose <p>Survivors of pediatric acute lymphoblastic leukemia (ALL) face long-term health challenges partially explained by treatment-related and cancer-related systemic inflammation. Beyond these effects, biobehavioral frameworks for understanding morbidity among survivors posit that other modifiable factors (e.g., emotional distress) influence systemic inflammation. These frameworks have not been explored within pediatric populations and do not consider potential caregiver impact. This study aimed to examine associations of caregiver factors and biobehavioral domains with systemic inflammation in survivors of pediatric ALL.</p> Methods <p>Survivors of ALL (<i>n</i> = 48), &gt; 5&#xa0;years from diagnosis, provided blood samples to assess C-reactive protein (CRP), a biomarker of inflammation. Caregivers completed measures of caregiver strain, caregiver distress, and survivor internalizing symptoms. Multivariable models examined associations between survivor internalizing symptoms, caregiver strain, and caregiver emotional distress on CRP. Interaction effects between predictor variables and age were tested in each model. Post hoc analyses assessed the relationships at the 16th (pre-adolescent), 50th (adolescent), and 84th (older adolescent) percentiles for participant age.</p> Results <p>Internalizing symptoms (<i>β</i> = .10, <i>p</i> = 0.01) and caregiver emotional distress (<i>β</i> = .08, <i>p</i> = 0.06) were associated with CRP levels in older adolescent survivors. Caregiver strain was associated with CRP levels among younger (<i>β</i> = .06, <i>p</i> = 0.01) and older adolescent survivors (<i>β</i> = .12, <i>p</i> = .002).</p> Conclusions <p>These findings suggest that developmental stage may moderate the impact of emotional and environmental stressors on systemic inflammation.</p> Implications for Cancer Survivors <p>These findings demonstrate the importance of follow-up care for caregivers and survivors during survivorship to support better physical and mental health outcomes.</p>