ObjectiveChildren in families with parental cancer may experience emotional, social or physical problems. The aims are to analyze child, parent and family‐based determinants of children's health‐related quality of life (HRQoL) and their experiences of parental cancer.MethodsAs part of a mixed‐methods, multicenter, prospective, interventional non‐randomized study “Family‐SCOUT,” a family‐centered intervention in the form of care and case management was developed. Children's HRQoL (KIDSCREEN‐10) was assessed at baseline (study inclusion). Descriptive analyses and family cluster‐adjusted linear mixed models were performed. Qualitative coding of children's experiences reported in an open‐ended text field of the questionnaire was performed.ResultsFour hundred and seventy‐two families with 472 parents with cancer and 649 children were included in the study of which N = 346 were analyzed. The average age of the children was 12.8 years. 48% of the children were female. Family cluster‐adjusted mixed linear model showed significant associations between children's HRQoL (dependent variable) and children's age (−0.44, p = 0.023, 95%‐CI = −0.82 to −0.06) and between families (ICCnull model = 0.377, Pseudo‐R2 = 0.443). Children experienced changes in the family situation, such as daily routines and communication among all family members, death of a parent, COVID‐19‐related difficulties, and supportive social relationships.ConclusionsChild, parent and family‐based factors appear to be related to children's HRQoL. Research on children's HRQoL and experiences in the context of parental cancer underscores the need for a multidimensional and family‐based approach to support these children.