Leukemia is the most common cancer among children. With the advancement of diagnostic techniques, most patients can achieve long-term survival. Many studies have begun to explore how serious games can be used as health intervention tools to help children with leukemia and their families improve health management skills. However, due to factors such as prolonged hospitalization, the impact of the disease, and treatment methods, children’s cognitive functions are affected, which may further impair their experience and adherence to serious games. Therefore, this study aims to explore the appropriate level of game design elements in serious games that align with the cognitive abilities of children with leukemia, along with corresponding design principles. Through preliminary literature review, this study identifies that cognitive deficits in children with leukemia primarily affect attention, executive function, and working memory. Based on this, a basic framework of serious game design elements was developed, focusing on elements relevant to these core deficits, which have not been specifically studied for children. A between-group experiment was conducted with children with leukemia to measure the appropriate levels of core design elements. The results show that for children with leukemia, the optimal mode of information delivery is a multimodal combination of text, animation, and sound; the suitable core attention span is approximately 13–15 mins; and the ideal number of elements that can be focused on within a single interface is six. The experimental results validate the impact of disease and treatment on cognitive impairments and provide appropriate levels for the core design elements. The findings offer valuable guidance for designing serious games targeted at children with leukemia.