This study aimed to examine the direct and indirect effects of hope on health-related quality of life (HRQoL) via anxiety of children/adolescents with cancer. We proposed to test if the mediation model was moderated by the child/adolescent's treatment status. The participants were 211 children/adolescents diagnosed with cancer, divided into two clinical groups according to treatment status: 97 patients on-treatment and 114 off-treatment. Self-reported questionnaires measured the youths' hope, anxiety, and HRQoL perceptions. The results revealed that children/adolescents on- and off-treatment only differed in levels of HRQoL, with a more compromised HRQoL found for the on-treatment group. Hope was positively associated with HRQoL, directly and indirectly via anxiety reduction. Moreover, only the association between anxiety and HRQoL was moderated by clinical group, revealing stronger associations for on-treatment patients. Findings highlight the importance of hope as a decisive resource in pediatric cancer adaptation, which may be strategically targeted in psycho-oncological interventions.