The study aimed to assess the prevalence of parental perceptions of a child’s vulnerability (PPCV) in a Dutch community-based sample and its relationship with children’s health and health-related quality of life (HRQoL). Parents completed the Child Vulnerability Scale and a socio-demographic questionnaire. The Pediatric Quality of Life Inventory 4.0 was administered to measure HRQoL. The prevalence of PPCV was assessed in relation to socio-demographic and health-related characteristics. In a three-step multiple hierarchical regression model, the mediational role of PPCV in the association between chronic illness and HRQoL was investigated. Participants were 520 Dutch children aged 5–18 years from nine Dutch schools. In all, 69 (13.3%) had a chronic illness; 1.9% was perceived vulnerable, 3.0% in groups 5–7 and 1.7% in groups 8–12 and 13–18. Younger age of the child, presence of a chronic illness and low HRQoL were associated with PPCV. PPCV partially mediated the negative association between chronic illness and HRQoL. In conclusion, PPCV is associated with adjustment to chronic illness. More research is needed regarding the mechanisms through which PPCV affects HRQoL and to examine whether PPCV can be targeted in parenting interventions.