Objectives: Thalassemia major (TM) is a chronic hematological disease that can have deep effects on patients’ mental health and psychological well-being. So, the present study was conducted to determine the effects of happiness training on the psychological well-being of TM patients. Methods: This quasi-experimental study with a pre/post-test design was performed on 52 patients with TM in Zabol city (Iran) from August to December 2020. The patients were randomly categorized into experimental and control groups. In the experimental group, happiness training was performed in eight sessions, each for 60 minutes. The control group received routine care. The data collection tool was the Ryff's Scale of Psychological Well-being (RSPWB). Data were analyzed by SPSS 16 statistical software using descriptive (mean and standard deviation) and inferential (paired and independent t-test) statistics. Results: Regarding the psychological well-being score at the pre-test stage, there was no statistically significant difference between the intervention (74.92 ± 6.36) and control (74.57 ± 5.83) groups (p = 0.83). After the intervention; however, a statistically significant difference was observed between the two groups in terms of psychological well-being (p <0.001). Also, a statistically significant difference was seen comparing the psychological well-being score between the pre- and post-intervention phases in the experimental (p = 0.01) but not control (p = 0.12) group. Conclusion: The results of this study showed that happiness training improved TM patients’ psychological well-being. Therefore, this type of training can be used as an appropriate educational strategy to improve psychological well-being in these patients.Keywords: Happiness; Education; Mental Health; Thalassemia.