Diagnosis of breast cancer is a devastating psychological experience for a woman. Also, treatments such as radiation therapy may cause psychosocial distress in these patients and threaten their quality of life (QOL). Among several approaches, spirituality has been shown to be significantly associated with improving the QOL. The aim of this study was to assess the role of spiritual therapy intervention in improving the QOL of patients with breast cancer undergoing radiation therapy. This was a randomized controlled trial study undertaken in a radiotherapy clinic, Isfahan, Iran. Between October 2010 and February 2011, 68 patients under radiation therapy were randomized to either spiritual therapy intervention group or control group who received routine management and educational programs. Before and after six weeks of spiritual therapy sessions, the QOL was evaluated using Cancer quality-of-life questionnaire (QLQ)-C30 and breast cancer-specific questionnaire (BR-23). Multivariate, repeated-measures ANOVA, t-test, and Paired t-test were used for analysis using Predictive Analytic Soft Ware (PASW, version 18) for windows. In all, 65 patients actually completed the six-week intervention and were evaluated for the outcome. The mean Global health status score/QOL reached from 44.37 (SD = 13.03) to 68.63 (SD = 10.86), (p = 0.00). There was a statistically significant difference in all functional scales of QLQ-C30 after intervention (p < 0.05). The results of this trial showed that the spiritual therapy program can improve the overall QOL of women with breast cancer; therefore, it could be adopted in comprehensive care programs for women with breast cancer.