Siblings demonstrate variable psychosocial adjustment to childhood cancer, ranging from cancer-related post-traumatic stress symptoms (PTSS) to resilience. Theoretical frameworks suggest that PTSS are influenced by appraisals (e.g., fear of mortality) and coping. Siblings’ presence within clinical settings and participation in cancer treatment may allow them to appraise cancer-related experiences as less threatening and utilize engagement coping strategies, but the nature and effect of siblings’ involvement in cancer treatment remains unknown, especially in the context of COVID-19. This mixed-methods research (a) characterized siblings’ involvement in cancer treatment, (b) investigated how siblings’ involvement in cancer treatment, demographics, cancer characteristics, appraisals and coping relate to PTSS, and (c) characterized COVID-19’s impact on siblings. Thirty-eight participants (22 siblings, 16 parents) from 16 families of youth with cancer completed qualitative interviews and quantitative measures. Study 1 qualitatively illustrated treatment involvement. Within the hospital and clinic, siblings emotionally supported patients, observed treatment, and learned about cancer. At home, siblings continued to support patients, assumed helper roles with treatment, and adjusted to new cancer-induced norms (e.g., family diet, cleaning practices). Study 2 used a cross-sectional, convergent, mixed methods design to identify factors related to siblings’ PTSS. Quantitative analyses revealed that siblings’ PTSS were significantly related to siblings’ age, appraisals and coping strategies. Mixed methods analyses showed that siblings who qualitatively described more consistent involvement in treatment, including access to information and opportunities to express emotions, had lower quantitative PTSS scores. Study 3 qualitatively described siblings’ treatment involvement and experience of cancer in the context of COVID-19. Siblings worried about contracting and transmitting COVID-19 to patients, but also described that cancer-related experiences prepared them for pandemic-related precautions. Due to increased time at home, siblings encountered more cancer reminders and had fewer opportunities to “take a break” from cancer. Siblings’ exclusion from clinical settings led to reduced understanding of cancer and increased cancer-related stress. Together, findings suggest that treatment involvement offers opportunities for siblings to process cancer-related cues and use engagement coping techniques, which may facilitate positive adjustment to cancer. Findings have important clinical implications related to (re)establishing family-centered care practices that explicitly include siblings.