Objective Children with life-threatening medical conditions frequently undergo invasive medical procedures that may elicit anxiety and distress. However, there are few empirically validated interventions that reduce mental health symptoms and increase the resilience of children during the acute stages of illness. This study aimed to evaluate the efficacy of the Make a Wish intervention for children with life-threatening cancer. Methods The design was a wait-list-controlled trial with two parallel groups. Sixty-six children aged 5–12 with an initial diagnosis of life-threatening cancer were identified and randomly assigned to the Make a Wish intervention (n = 32) or a wait-list control group (n = 34). Children completed measures of psychiatric and health-related symptoms, positive and negative affect, hope, and optimism pre-intervention and post-intervention. After baseline data collection, children were interviewed and made an authentic wish that they wanted to come true. These wishes were made possible 5–6 months after baseline data collection, to fuel anticipation and excitement over the wish-fulfillment event. The post-intervention assessment point was 5 weeks after wish fulfillment (approximately 7 months after baseline data collection). Results Children in the intervention group exhibited a significant reduction in general distress (d = 0.54), depression (d = 0.70), and anxiety symptoms (d = 0.41), improved health-related quality of life (d = 0.59), hope (d = 0.71), and positive affect (d = 0.80) compared to decrease in positive affect and no significant changes in the other measures in the control group. Conclusions These findings emphasize the role of hope and positive emotions in fostering the well-being of children who suffer from serious illnesses.