Background: β-Thalassemia major is a chronic transfusion-dependent genetic disorder that imposes substantial physical, psychological, social, and economic burdens on caregivers. In India, particularly in West Bengal, evidence on caregiver quality of life (QOL) remains limited.

Objective: To assess QOL across physical, psychological, social, and environmental domains among caregivers of children with β-thalassemia major, and to identify associated socio-demographic factors.

Methods: A hospital-based cross-sectional study was conducted from January to October 2023 at the inpatient department of the Thalassemia Clinic, Burdwan Medical College & Hospital, West Bengal. A total of 372 primary caregivers of children aged 1–10 years with β-thalassemia major were selected by simple random sampling. Data were collected using a pretested semi-structured schedule and the validated Bengali version of the WHOQOL-BREF. Descriptive statistics, Mann–Whitney U test, and Kruskal–Wallis test were applied using SPSS v23.

Results: The mean global QOL score was 52.3 ± 6.8, with the highest domain score in psychological health (54.2 ± 8.2) and the lowest in environmental health (48.7 ± 6.1). Lower QOL was significantly associated with caregiver age >30 years, male gender, Muslim religion, lower caste, lower education, low socio-economic status, joint family type, widow/separated marital status, younger child age, female child gender, and higher transfusion frequency (all p < 0.05). Socio-economic status, education, and caregiver age emerged as the strongest determinants of QOL.

Conclusion: Caregivers—predominantly mothers—exhibit moderate QOL, with environmental and social domains most affected. Interventions focused on financial support, caregiver education, mental health counselling, and enhanced social assistance are warranted.