Background: As an alternative to hospitalization, home healthcare programs are assuming greater significance on a global scale due to the expanding geriatric population and the prevalence of chronic and acute diseases that require ongoing monitoring and care. In describing and evaluating the quality of life (QOL) and associated determinants of patients enrolled in the Home Health Care (HHC) program affiliated with the Ministry of National Guard Health Affairs in Riyadh, Saudi Arabia, was the overarching purpose of this study. Methods: Participants in this cross-sectional study were HHC program enrolled patients. Utilizing the World Health Organization QOL questionnaire (WHOQOL-BREF), information regarding the various domains of patients' QOL was gathered. By fitting logistic regression models, factors associated with a low QOL score were identified. Results: In the research, 253 patients participated. Age distribution: 67.05 (± 20.0). Morbid and sociodemographic characteristics had a substantial impact on the overall quality of life of HHC patients. The final multivariate logistic regression models identified independent associations between marital status, psychological disorders, stroke, and number of illnesses and the overall quality of life (QOL) of HHC patients (p =.022, p =.002, p =.031, and.057, respectively). In a retrospective analysis, the physical health domain score exhibited significant associations with educational attainment, psychological issues, and stroke (p =.028, p =.002, p =.007). Conversely, the psychological domain score demonstrated a significant association with age (p < 0.001) and three distinct forms of chronic ailments—pulmonary (p =.002), psychological problems (p = 0.001), and p =.002. Only the marital status exhibited a significant association with the social domain score (p =.026). There was a significant association between the environmental domain and both education level and stroke incidence (p =.017 vs..027). Conclusions: Multiple factors are substantially correlated with the overall QOL and its domains. A significant number of these factors can be monitored and improved by enhancing the efficacy of HHC services; consequently, this will enhance patients' QOL.