BACKGROUND As a precarious clinical condition and a public health problem, heart failure (HF) is associated with a significant burden of morbidity, mortality, and health care costs. As almost all of the published research has been conducted in Western countries, there is a need for culturally relevant studies in Saudi Arabia. This is the first study to investigate health-related quality of life (HRQoL) and its associated factors among Saudi patients with HF in the Qassim region. METHODS A cross-sectional study was conducted at the only tertiary care hospital in the Qassim region of Saudi Arabia during the period from November 2020 to July 2021. The participants were interviewed face-to-face by trained interviewers using the standard validated 36-item Short-Form Health Survey (SF-36) questionnaire for HRQoL assessment. The data were analyzed using STATA version 16. RESULTS The participants included 246 HF patients whose mean (SD) age was 56.7 (10.9) years. A majority of the respondents (80%, n = 197) were male, and 49% (n = 121) had an education level of less than secondary school. The median scores were high for the domains of social functioning (100 points) and bodily pain (75 points) and low for role-physical functioning (25 points). In general, the median scores for the physical and mental component summaries were 58.1 and 63.7, respectively. Patients with an education level less than secondary school were more likely to have a low physical component summary score (aOR 3.00, 95% CI 1.46-6.17), while female patients were more likely to have a low mental component summary score (aOR 2.67, 95% CI 1.38-5.16). CONCLUSIONS Health-related quality of life was found to be moderate among these HF patients. Periodic HRQoL assessment is recommended for HF patients to minimize their physical and psychological concerns, particularly for patients with low education levels and female patients.