Objective: To assess the relationship between care giver burden, hopelessness and Psychological distress. To explore the impact of care giver burden on Psychological distress and mediating role of hopelessness among carers of Thalassemia patients. Study Design: Descriptive cross-sectional study. Place and Duration of Study: At the Thalassemia center of The Children’s Hospital & the Institute of Child Health Multan, Pakistan, in seven month from 17th November 2018 to 26th March 2019. Material and Methods: Two hundred and forty (240, 48.3% males and 51.6% female) carers of Thalassemia patients were assessed on Burden Scale for Family Caregivers (BSFC), Kessler Psychological Distress Scale (K10) and Beck Hopelessness Scale (BHS). Results: Findings showed that caregiver burden was positively correlated with psychological distress (p<0.01) and hopelessness (p<0.01). Results also revealed that caregiver burden significantly positively predicted hopelessness (p<0.00) and hopelessness mediated the relationship between care giver burden and psychological distress (p<0.00). Outcomes also illustrated that there were differences on care giver burden (p<0.01), Psychological distress (p<0.00) and hopelessness (p<0.00) among carers of patients with thalassemia disorders on the ground of carer’s gender. Conclusion: Care giver burden, Psychological distress and Hopelessness are interlinked phenomenon, while male have more hopelessness and female have more care giver burden and psychological distress.