Haploidentical transplantation strategies for patients with transfusion‐dependent thalassaemia (TD‐TM) remain to be investigated. In this study, 54 paediatric patients with TD‐TM were treated with a novel approach using post‐transplant cyclophosphamide (PTCy) and low‐dose methotrexate (LD‐MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II–III acute graft‐versus‐host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow‐up of 520 days (132–1325 days), the overall survival (OS) and event‐free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low‐dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high‐CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II–III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD‐MTX in TD‐TM are encouraging. (chictr.org.cn ChiCTR1800017969)