Background Health-related quality of life (HRQoL) is one indicator of successful treatment of children's leukemia. It was influenced by many factors, including family management, one of the family variables. According to the family management framework, family management is a mediator that mediates between several factors and the health-related quality of life of children with specific diseases. This study aimed to evaluate mediating effects of family management on the relationship between several contextual influences and pediatric HRQoL of families with leukemia children in Indonesia. Methods This cross-sectional study involved parents of children with leukemia during active treatment recruited by purposive sampling from three hospitals in Java Island, Indonesia, starting from January 2021 to May 2022. Parents answered the questionnaire and interview to evaluate family management, Pediatric Quality of Life Inventory™ Cancer Module (PedsQL-C) to measure children’ HRQoL, the Multidimensional Illness Severity Questionnaire used to investigate the disease severity, and the Multidimensional Scale of Perceived Social Support to assess the social support. Descriptive statistics and path analysis were used to analyze family management as a mediator between family income, family structure, social support, geographic location, age of child, severity of disease, and HRQoL as the response variable. Results Based on 202 parents who completed the questionnaire found that social support and the severity of the disease significantly influenced both components of family management. Social support positively affected Easy Family Management (EFM) (β = .330, p = .000), while the severity of disease negatively influenced EFM (β = − .342, p = .000). In contrast, social support negatively affected Difficulty in Family Management (DFM) (β = − .137, p = .006), and severity of disease positively influenced DFM (β = .384, p = .000). Moreover, both of EFM and DFM had mediated the only relationship between severity of disease and health-related quality of life with p-value < 0.05. Conclusion This study partially supported the Family Management Style Framework. Social support and family management as modifiable factors should be adjusted to develop specific interventions and strategies to improve the quality of life of children.