Caregiving and living with a Down Syndrome (DS) child is distressing and has given a negative impact on the quality of life of parents. The study aims examine the parents with DS children on the health-related quality of life (HRQoL) and family functioning and to identify potential factors affecting them. The cross-sectional study involved 94 parents with DS children from the Paediatric Clinic, Hospital Raja Perempuan Zainab II, Kota Bharu, Malaysia, with a mean age of 46.7 ± 7.0 years. Demographic and socioeconomic data of the parents and DS children were collected, and their quality of life (QoL) was measured based on the self-reported Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM). Parents of DS children in the current study have shown good HRQoL and family functioning, with scores of 83.2 and 89.3 out of 100, respectively. The family functioning score shown significantly correlated with the parental health-related quality of life (p<0.001). The number of family members was found to have a statistically significant effect on family functioning (p=0.015). The lowest score in the HRQoL was in the domain of ‘worry’. The findings of the current study verify previous reports of relatively good quality of life and family functioning in families with DS children and also with other disabilities.