Background: Although heart failure (HF) is negatively known to affect older adults physically, psychologically, and socially, only a few studies have explored the predictors of quality of life (QoL) in older adults with HF in Taiwan. Purpose: This study was designed to determine the relationships among depression, demographic characteristics, clinical characteristics, and QoL in older patients with HF. Methods: This was a cross-sectional study. From January 2013 to June 2014, convenience sampling was used to collect data from 175 older adults with HF at two hospitals in Northern Taiwan. Participant data were collected from medical records and researcher-administered structured questionnaires in face-to-face interviews. Results: The QoL of the participants was found to be associated with clinical characteristics, including hospital readmission for > 10 days with an increased level of HF-related symptom distress (HFSD) and more-severe depression. Depression was found to have a mediating effect, with the New York Heart Association (NYHA) functional class and HFSD both affecting the QoL of the participants through this intermediary. Conclusions/Implications for Practice: HF is a chronic and debilitating disease that often reduces QoL in older adults significantly. Interventions designed to increase QoL by improving the NYHA functional class and alleviating HFSD are valid treatment options only in cases with depressive symptoms. Nurses treating older adults with HF should consider factors such as NYHA functional class and HFSD to reduce HFSD and readmission rates and to enhance the QoL of these patients. In addition, after both hospital admission and discharge, older adult patients should be assessed regularly to monitor for and quickly address the development of comorbid depression.