The aim of this study was to explore the digital game-based learning for children with chronic illnesses in the hospital settings. The design-based research and qualitative methods were applied. Three eight-year-old children with leukemia participated in this study. In the first phase, the multi-user game-based learning system was developed and implemented during the first iteration. Children could create their own or co-construct narratives and play mathematics games in the multi-user system. Then, we developed the multi-modal digital game-based learning activities in the second iteration. Children showed highly motivation to engage in learning activities. A list of key design features related to the digital game-based learning for children with chronic illnesses emerged from the data. The results supported that the multi-modal digital game-based learning provided the social interactive processes and learning motivation, which effectively served the learning and psychosocial needs of chronically ill children.