Background <p>Burden influences caregiving experiences for family caregivers and patients. While family caregivers are crucial in end-of-life, their burden remains under-researched, particularly regarding the role of spiritual intelligence in shaping this experience.</p> Objectives <p>To explore the level and type of burden of family caregivers of palliative adult cancer patients and its relationship to variables related to: caregiver; patient; and caregiving process; exploring associated factors of burden.</p> Methods <p>A quantitative, cross-sectional study including adult, unpaid, primary family caregivers providing support in at least one daily life activity to adult cancer patients. Caregiver burden was assessed using the Zarit Caregiver Burden Scale and spiritual intelligence through Spiritual Intelligence Self-Assessment Inventory. Linear regression analysis was used to examine significant relationships. The study followed the STROBE guidelines for reporting observational research and ethical procedures were ensured.</p> Results <p>The mean burden level was intense, predominantly on burden subdimension “Expectations Towards Caregiving”. Significant correlations were found between burden and caregiver age, social support, financial status, caregiver having chronic diseases or being on pain medication and resilience. The multivariable model identified key associated factors: caregiver’s older age, having no social support, having other dependents, and lower resilience, explaining approximately 40% of the burden. Spiritual Intelligence subdimension of “Personal Meaning Production” was associated with lower burden on “Self-efficacy Perception” subdimension.</p> Conclusions <p>Family caregivers face specific struggles. Policies should provide structured support and financial resources. Interventions to prevent burden should include resilience and spiritual intelligence training, aiming to improve caregivers’ self-efficacy.</p>