Background: Evaluation of factors influencing scales of burden, coping mechanisms, and quality of life (QOL) in caregivers of hemodialysis (HD) patients may lead to the revision of interventions aimed at the betterment of QOL of caregivers of HD patients. In this study, we investigated the influence of demographic, social, and clinical variables on burden, coping mechanisms, and QOL in caregivers of HD patients. Methods: In this prospective study, 150 caregivers of HD patients were recruited. Assessment of burden, coping strategies, and QOL were made by the Zarit Burden Interview, Revised Ways of Coping, and Short Form-36 QOL. The role of age, gender, and social and clinical variables on these constructs was investigated using multivariate analysis of variance. Results: The mean age was 43.86 ± 1.11 years. Males outnumbered females. Most were Hindu, married, primary school educated, unemployed, spouses, caring the patients, and suffering from chronic diseases for <5 years. In multivariate analysis of variance, effect of age on physical functioning (PF), general health (GH), and physical component summary (PCS) score (P < 0.01); gender on burden, distancing, seeking social support, role limitation due to emotional problem, and pain (P < 0.05); role limitations due to physical health, energy/fatigue (EF), emotional well-being, PCS, and mental component summary (MCS) score (P < 0.01); religion on PF (P < 0.05); marital status on burden and GH (P < 0.05); PF and PCS (P < 0.01); relationship of caregiver with the patient on PCS (P < 0.05); EF and MCS (P < 0.01); and presence of chronic diseases on GH and social functioning (P < 0.01) were observed. Conclusion: The role of demographic, social, and clinical variables should be taken into consideration while initiating therapies for reducing the burden and improving the QOL of caregivers.