Aims To develop a comprehensive understanding of caregiver burden and its predictors from a dyadic perspective. Method A convergent mixed methods design was used. This study was conducted in three European countries, Italy, Spain, and the Netherlands. A sample of 229 HF patients and caregivers was enrolled between February 2017 and December 2018 from the internal medicine ward, outpatient clinic, and private cardiologist medical office. In total, 184 dyads completed validated scales to measure burden, and 50 caregivers participated in semi-structured interviews to better understand the caregiver experience. The Care Dependency Scale, Montreal Cognitive Assessment, and SF-8 Health Survey were used for data collection. Multiple regression analysis was conducted to identify the predictors and qualitative content analysis was performed on qualitative data. The results were merged using joint displays. Results Caregiver burden was predicted by the patient’s worse cognitive impairment, lower physical quality of life, and a higher care dependency perceived by the caregivers. The qualitative and mixed analysis demonstrated that caregiver burden has a physical, emotional, and social nature. Conclusions Caregiver burden can affect the capability of informal caregivers to support and care for their relatives with heart failure. Developing and evaluating individual and community-based strategies to address caregiver burden and enhance their quality of life are warranted.