Children with thalassemia can thrive with quality care by their families. The purpose of this study was to examine predictors of family care behavior by family caregivers of children with thalassemia. Eighty-eight family caregivers for children with thalassemia aged 1-16 years were recruited by purposive sampling from in-patient and out-patient clinics in an eastern regional hospital in Thailand. Research instruments were 5 self-administered questionnaires: 1) demographics of family caregivers, 2) perceived family management, 3) medical adherence, 4) health literacy, and 5) family management behavior. Data were analyzed by percentages, means, standard deviations, Pearson's product moment correlation and multiple regression. The strongest predictor for family management behavior was perceived family management (B = 0.550, p < 0.001), it accounted for 26.3% of the variance. Health literacy (B = 0.337, p = 0.024) accounted for 4.5% of the variance. When these two dependent measures were combined, they accounted for 30.8% of the variance (R2 = 0.308, F = 18.933, p < 0.001). Within the three subscales of family management behavior (medical, role, and psychosocial management), medical adherence, health literacy and perceived family management, together accounted for 22.6% of the variance for medical management. Perceived family management and health literacy together accounted for 30.3% of the variance in role management. Perceived family management accounted for 20.9% of the variance in psychosocial management. These findings suggest a tailored intervention program should emphasize promoting family management and increasing health literacy to improve the quality of family management behavior for children with thalassemia.