Objective <p>Children with transfusion-dependent thalassemia (TDT) face significant physical, emotional, and social challenges that affect their and their families’ lives. This study aimed to examine and compare the coping mechanisms of children with TDT and the disease-related impact on their parents’ functioning.</p> Methods <p>This study enrolled children with TDT aged 8–16&#xa0;years and age-matched healthy controls (ratio 1:2), and their respective parents. Psychological assessment of the children and their families was conducted using the PedsQL™ Family Impact Module and KidCOPE. Scores obtained from cases and controls were compared using the Mann–Whitney U test.</p> Results <p>Children with TDT (<i>n</i> = 75) showed significantly lower frequency of self-criticism (<i>P</i> = 0.001), higher perceived efficacy of problem-solving as a coping strategy (<i>P</i> = 0.008) and greater use of social support (<i>P</i> = 0.018) compared to the control group (<i>n</i> = 150). The respective parents of children with TDT experienced poorer overall family functioning and lower quality of life compared to parents of healthy children (<i>P</i> = 0.001).</p> Conclusions <p>The findings indicate that while children with TDT use certain adaptive coping strategies more frequently than their healthy peers, the overall family functioning and parental quality of life remain significantly compromised. These results highlight the need for psychosocial support addressing both child coping and caregiver well-being.</p>