Background: Fatigue is a prevalent and distressing symptom in children and adolescents with cancer. Objectives: This study aimed to (1) investigate the current fatigue status reported by Chinese children and adolescents with cancer during active cancer treatment and (2) examine whether sociodemographic information, disease and treatment information, co-occurring symptoms, function and related clinical data are significantly associated with fatigue according to the biopsychosocial model. Methods: Participants were children aged 8–17 years, who had undergone treatment for cancer at four hospitals in China. Children completed the Chinese version of the Pediatric Patient-Reported Outcomes Measurement Information System short forms. Results: In total, 187 children (33.16% female, mean age 10.28 years) participated. The mean T-score for child-reported fatigue was 48.52 (34–72). Multiple linear regression analysis showed that fatigue in pediatric active cancer treatment could be significantly predicted by greater child-reported pain interference (β = 0.391, p < .001), greater depressive symptoms (β = 0.443, p < .001), and reduced mobility (β = −0.226, p = .004) (adjusted R² = 0.613, F = 16.476, p < .001). Conclusions: Children and adolescents with cancer experience multiple, intersecting troubling symptoms during their treatment. There is a need to attend to the biopsychosocial aspects of care for children and adolescents during active cancer treatment. To reduce pediatric oncology patients’ fatigue level, clinicians could develop culturally sensitive interventions to alleviate children’s pain interference, treat depressive symptoms, and maximize their physical mobility.