BackgroundLifelong provision of care to chronically ill patients increase the risk of physical and mental diseases in informal caregivers and adversely affects their quality of life. The present study examined the correlation between caregiver burden, depression, and quality of life among the informal caregivers of thalassemia and hemodialysis patients during the COVID-19 pandemic in southeastern Iran.MethodsThis cross-sectional correlational study used convenience sampling to select 200 informal caregivers involved in providing direct care for patients undergoing hemodialysis (n = 70) and patients with thalassemia (130) for at least 6 months. A demographic questionnaire, Beck’s Depression Inventory (BDI), the Quality-Of-Life Questionnaire (SF-36), and the Zarit Burden Interview were used to collect data in 2021. The data were analyzed with SPSS software (version 19) using frequency, percentage, independent samples t-test, ANOVA, and multivariate regression analysis.ResultsMost of the informal caregivers of the thalassemia and hemodialysis patients (58% and 43%) reported moderate levels of caregiver burden. There were significant correlations between the caregiver burden and depression (P < 0.0001) and between the caregiver burden and the quality of life (P < 0.009). The level of depression in informal caregivers of patients undergoing hemodialysis was higher than that of the informal caregivers of patients with thalassemia, but the quality of life in the informal caregivers of the patient’s undergoing hemodialysis was higher than that of the informal caregivers of the patients with thalassemia.ConclusionConsidering the significant correlations between caregiver burden, depression, and quality of life in this study, healthcare providers are recommended to develop educational and supportive interventions to meet informal caregivers’ needs, mitigate their emotional distress, fears, and concerns, and prevent caregiver burden in times of greater uncertainty.