Purpose: Previous research incorporating yoga (YG) into radiotherapy (XRT) for women with breast cancer finds improved quality of life (QOL). However, shortcomings in this research limit the findings. Patients and Methods: Patients with stages 0 to III breast cancer were recruited before starting XRT and were randomly assigned to YG (n = 53) or stretching (ST; n = 56) three times a week for 6 weeks during XRT or waitlist (WL; n = 54) control. Self-report measures of QOL (Medical Outcomes Study 36-item short-form survey; primary outcomes), fatigue, depression, and sleep quality, and five saliva samples per day for 3 consecutive days were collected at baseline, end of treatment, and 1, 3, and 6 months later. Results: The YG group had significantly greater increases in physical component scale scores compared with the WL group at 1 and 3 months after XRT (P = 0.01 and P = 0.01). At 1, 3, and 6 months, the YG group had greater increases in physical functioning compared with both ST and WL groups (P < 0.05), with ST and WL differences at only 3 months (P < 0.02). The group differences were similar for general health reports. By the end of XRT, the YG and ST groups also had a reduction in fatigue (P < 0.05). There were no group differences for mental health and sleep quality. Cortisol slope was steepest for the YG group compared with the ST and WL groups at the end (P = 0.023 and P = 0.008) and 1 month after XRT (P = 0.05 and P = 0.04). Conclusion: YG improved QOL and physiological changes associated with XRT beyond the benefits of simple ST exercises, and these benefits appear to have long-term durability.