Background Patients with the thalassemia have a basic requirement for self-efficacy regarding their treatment procedure. The present study aimed to compare the effect of self-care education via a smartphone application and lectures on the self-efficacy of patients with thalassemia. Methods In the present quasi-experimental study, 99 patients with thalassemia at Shahid Beheshti Hospital in Yasuj, Iran, in 2019 who were eligible to enter the study, were selected. The block randomization was done with the block sizes of 3, 6, and 9, and participants were randomly assigned to 3 groups: smartphone application (A), lecture intervention (B), and control (c). Smartphone application and lecture interventions were performed for intervention groups A and B, respectively, during 8 weeks. Scherer's self-efficacy measure was used to collect the data at baseline and eight weeks after the intervention. Data were analyzed by SPSS-version 25 software using Paired t-test, Wilcoxon and Kruskal–Wallis tests. Results Ninety-nine patients with thalassemia with a mean (SD) age of 25 (6) and 58 females (58.59%) participated in the present study. The results indicated a significant difference in self-efficacy among 3 groups after intervention (P = 0.001). However, self-care education with smartphone application revealed a significant increase in the mean (SD) of self-efficacy of the patients with thalassemia 68.36(8.45) compared to the lecture method 62.55 (7.3) (P = 0.003) and control 62.09 (6.7) (P = 0.001). There were no significant differences among the self-efficacy scores of the patients in lecture intervention and control groups. Conclusions The results revealed that smartphone application was a suitable educational software to promote self-efficacy in patients with thalassemia. It is recommended to use smartphone application methods to improve the self-efficacy levels of patients with thalassemia.