To examine predictors of health-related quality of life (HRQoL) for caregivers of children with developmental disabilities, a cross-sectional design was used. Participants were primary caregivers of children with developmental disabilities. Caregivers completed a demographic form about the child and the family, and the Arabic version of Patient-Reported Outcomes Measurement Information System-Profile 29 (PROMIS-29 v2.0). Descriptive statistics were used to report on demographic data, 1-sample Z tests to compare PROMIS domain scores with the general population, and multiple linear regression analyses to identify predictors of each domain. Participants were 111 primary caregivers, mostly mothers (65.8%). Caregivers reported higher levels of anxiety, depression, fatigue, sleep disturbance, and pain interference, and lower levels of physical function and social participation compared to the general population, P < .05. The regression models for predicting the HRQoL accounted for 12.3% of the variance in the physical function domain (P = .016), 13.9% in the anxiety domain (P = .009), 24.7% in the ability to engage in social activities and roles (P < .001), and 11.4% in the pain interference domain (P = .02). In these models, the severity of the child's disability and/or the child's age were common significant predictors. Specifically, child's age was the only significant predictor in 2 domains, the anxiety domain (β = -.29, P < .01) and ability to participate in social activities and roles domain (β = .42, P < .05). The severity of the child's disability was the only significant predictor in the physical function domain (β = -.52, P < .01). Both the severity of the child's disability and the child's age were significant predictors in the pain interference model (β = .40, P < .05), and (β = -.23, P < .05), respectively. However, the models did not significantly predict depression, fatigue, or sleep disturbance, P > .05. HRQoL is a complex construct and is influenced by multiple child and family factors. Implications of the study emphasize the importance of regular HRQoL screening for caregivers, the development of efficient referral systems for support services, and the exploration of respite care options.