Background: A child's disability affects not only that child but also their caregivers. This study compares the quality of life (QoL) of Saudi mothers (primary caregivers) of children with Cerebral Palsy (CP) and Down Syndrome (DS) and mothers whose children do not have a disability, and explores its relationship with socioeconomic status. Methods: Two hundred mothers of children with disabilities and 99 mothers of children without disabilities were recruited from rehabilitation centers and regular schools, respectively. Information on their sociodemographic, social support, and QoL information was collected using the Quality of Life Index (QLI) – Generic Version III. Results: The independent-samples t-test and Welch's test for QoL indicate that the mothers of children with disabilities have less satisfaction (QLI Part 1) in the social and economic subscale compared to the mothers of children without disabilities (p = 0.0068) but no differences were found in the other domains. For QLI Part 2 (Importance), the mothers of children with disabilities were found to attribute more importance to health and functioning than mothers of children without disabilities (p = 0.003). The former were also found to attribute less importance to their psychological/spiritual status than the latter (p < 0.01). There was no significant difference in total score or in the family or socioeconomic domains. Conclusions: It is concluded that Saudi mothers of children with disabilities need more social support and professional help to improve their quality of life.