The complexity of palliative care means that the emotional distress and burden that primary family caregivers suffer under can be particularly high. The objective of this study was to determine the level of burden endured by these primary family caregivers and to identify the variables that predict it in the caregiving relatives of people who require home-based palliative care. A descriptive-correlational cross-sectional study was conducted. Socio-demographic and clinical data were collected from caregivers through a self-administered questionnaire that included questions from the 12-Item Short Form Health Survey (SF-12), Zarit Caregiver Burden Interview (ZBI), Hospital Anxiety and Depression Scale (HADS), Brief Resilient Coping Scale (BRCS), Post Traumatic Growth Inventory (PTGI), and Fatigue Assessment Scale (FAS). A total of 77 caregivers participated; 66.2% were women, and the mean age was 61.5 years. Most (62.3%) were providing care to cancer patients. From among these data, the presence of anxiety as a clinical problem (48.1%), a high average fatigue score (FAS) of 23.0 (SD = 8.5), and the prevalence of intense overload (41.6%) stood out. We found statistically significant correlations between the variables of burden, fatigue, post-traumatic growth, anxiety, and depression, with the latter two being the main predictive variables of burden. In addition, caregiver burden was associated with a worsening of health. Identifying the factors that influence the appearance of overburden will allow the specific needs of careers to be assessed in order to offer them emotional support within the healthcare environment.