Background: This study examines the role of illness perceptions and fear of progression (FoP) in paediatric cancer patients and their parents for patient’s health-related quality of life (HRQoL), controlling for sociodemographic and medical variables. 4–18-year-old patients in acute treatment or follow-up care and one parent were examined. Methods: N = 46 patient-parent dyads in acute treatment and n = 84 dyads in follow-up care completed measures on illness perceptions (Illness-Perceptions-Questionnaire for 12–18-year-old patients and parents or as age-adapted puppet interview for 4–11-year-old patients) and FoP (Fear-of-Progression-Questionnaire for 7–18-year-old patients and parents). Patients also completed the KINDL-R to measure HRQoL. Hierarchical multiple regression analyses were calculated. Results: In acute treatment, patient’s perceptions of symptoms and cyclicity of their illness explained variation in their HRQoL in addition to sociodemographic and medical variables. In follow-up care, patient’s FoP and parent’s perception of consequences explained additional variation in patient’s HRQoL. Overall, sociodemographic and medical variables explained less variation in HRQoL in follow-up care than in acute treatment. Conclusions: Our results stress the importance of psychological factors for the well-being of paediatric cancer patients, particularly in follow-up care, where sociodemographic and medical variables play a lesser role. We recommend screening for illness perceptions and FoP during and after acute treatment to support patients and parents. Furthermore, standardized interventions focussed on changing maladaptive illness perceptions should be developed and evaluated. As parents’ perceptions, thoughts, and feelings may also play an important role for the well-being of the patients, interventions should be family-focussed and include parents. Trial registration The study has been pre-registered at the German Clinical Trials Register (registered 30/06/2020; DRKS00022034) and at the Open Science Framework (https://osf.io/3uwrx).