Background: Many children with intellectual disability live with medical comorbidities. This study examined the impacts of comorbidities on quality of life (QOL) of children with intellectual disabilities and whether impacts varied with caregiver perceptions that medical needs had been met. Methods: Primary caregivers of 447 children (aged 5–19 years) with an intellectual disability reported on their child's medical comorbidities and the extent to which they perceived their child's medical needs had been met in a cross-sectional observational study. The Quality of Life Inventory-Disability was used to measure QOL on a 100-point scale. Linear regression models including interaction terms were used to evaluate their associations. Results: Parent-reported recurrent child pain (−4.97, 95% CI −8.21, −1.72), night-time sleep disturbances (−4.98, 95% CI −7.23, −2.73), daytime somnolence (−8.71, 95% CI −11.30, −2.73), seizures that occurred at least weekly (−7.59, 95% CI −13.50, −1.68) and conservatively managed severe scoliosis (−7.39, 95% CI −12.97, −1.81) were negatively associated with child QOL. Despite the majority of parents (~70%) perceiving that their child's medical needs had been met to a great extent, this did not significantly moderate the association between any comorbidities and QOL. Conclusions: Comorbidities were common and had marked associations with QOL. Evaluation and management of pain and sleep disturbance continue to be high priorities in improving QOL of young people with intellectual disabilities. Further research on the optimal methods of managing these comorbidities is warranted.