(1) Background: Long-term caregiving for patients receiving hemodialysis (HD), is associated with physical and psychological stress, which may impact on the well-being and quality of life of caregivers. Due to a lack of understanding of the experiences of informal caregivers of patients receiving HD, especially in Saudi Arabia, this study aimed to measure burden in informal caregivers of patients receiving HD, examine the factors that predict caregiver burden (CB), and explore the experience of burden in caregivers of patients receiving HD. (2) Methods: This study used a mixed-methods, sequential, explanatory design, which consisted of two phases. Phase 1 involved a cross-sectional study design, with a convenience sample of 61 caregivers of patients on maintenance HD for at least 3 months. All caregivers in the study completed the Arabic version of the Zarit Burden Interview to identify caregiver burden. Phase 2 of the study involved a qualitative descriptive design involving semi-structured interviews with nine caregivers. (3) Results: Study findings indicate that caregivers did not experience severe burden. Being older, a female caregiver and having comorbidities was positively associated with increased levels of caregiver burden. In the qualitative phase of the study, a number of important factors emerged that may contribute to a reduction in caregiver burden, including social support, cultural acceptance, and religious influences. (4) Conclusion and impact: CB was found to be low when a comparison was made with other studies using similar populations. Understanding the factors that influence caregiver burden will contribute to the accurate assessment of caregiver burden and help reduce burden in informal caregivers, patients with renal failure, and others with chronic illnesses worldwide.