The consequences of spinal cord injury (SCI) not only affect patients’ health-related quality of life (HRQoL) but also extend to the entire family. The health condition the injury imposes requires the participation of a family caregiver, who will be responsible for taking care of the individual in a disabling condition. This is an observational, exploratory study using a cross-sectional design that aimed to study the association between HRQoL and gender, age, presence of comorbidities, and characteristics of the care among caregivers of individuals with SCI with the purpose of identifying potential factors that are associated with HRQoL in this population. Participants were 59 caregivers of individuals with traumatic SCI. The data were collected by consulting the patient histories and applying questionnaires. To assess the caregivers’ HRQoL, the Short Form-36 was used. For analysis, exploratory and inferential statistics were used. Most of the caregivers of the individuals with SCI were female, with a mean age of 44.8 years. The domains that most contributed to a worse HRQoL were physical aspects, pain, vitality, and emotional aspects. No statistically significant associations were found between HRQoL and the variables gender, hours per day spent on care, and length of activity as caregiver. The associations between HRQoL and self-reported diseases and age were statistically significant. The results support the planning of nursing interventions from the perspective of aspects of the care demands, which can affect the caregiver’s HRQoL. Relevance to clinical practice: Interventions to prepare the individuals with SCI and their caregivers are a strategy aimed at improving the HRQoL of both.