Heart failure is a chronic disease requiring lifetime self-management at home by patients, who often require additional support. However, the long-term nature of this self-management presents great challenges for both heart failure patients and their family caregivers. The role of family caregivers is critical, but little is known about the relationship between the burden, stress, depressive symptoms, and quality of life in the family caregivers of heart failure patients. We aimed to explore caregiver burden, stress, depressive symptoms, and quality of life in both patients with heart failure and their family caregivers and identify the factors associated with family caregivers' quality of life. The sample included 120 participants (60 heart failure patients and 60 corresponding family caregivers) from cardiovascular outpatient clinics at 2 university-affiliated hospitals in South Korea from September 2018 to July 2019. The mean ages of the heart failure patients and their caregivers were 72.72 (SD = 12.73) and 57.03 (SD = 13.42) years, respectively. Caregiver burden (r = -0.601, P < .001) and caregiver depressive symptoms (r = -0.535, P < .001) were negatively correlated with the caregivers' quality of life. The result of the hierarchical multiple regression analysis identified 3 significant factors related to the family caregivers' quality of life: caregiver's age (beta = -0.257, P = .012), caregiver burden (beta = -0.408, P = .002) and caregiver depressive symptoms (beta = -0.298, P = .018), with overall explanatory power of 47.5%. It is necessary to develop practical strategies to improve family caregivers' quality of life by alleviating their burden and depressive symptoms. Healthcare providers should be engaged with not only heart failure patients but also their family caregivers during the disease management process to improve patients' outcomes.