Hypothesis This study examines moderators and mediators of a yoga intervention targeting quality-of-life (QOL) outcomes in women with breast cancer receiving radiotherapy.Methods Women undergoing 6 weeks of radiotherapy were randomized to a yoga (YG; n = 53) or stretching (ST; n = 56) intervention or a waitlist control group (WL; n = 54). Depressive symptoms and sleep disturbances were measured at baseline. Mediator (posttraumatic stress symptoms, benefit finding, and cortisol slope) and outcome (36-item Short Form [SF]-36 mental and physical component scales [MCS and PCS]) variables were assessed at baseline, end-of-treatment, and 1-, 3-, and 6-months posttreatment. Results Baseline depressive symptoms (P = .03) and sleep disturbances (P < .01) moderated the Group x Time effect on MCS, but not PCS. Women with high baseline depressive symptoms in YG reported marginally higher 3-month MCS than their counterparts in WL (P = .11). Women with high baseline sleep disturbances in YG reported higher 3-months MCS than their counterparts in WL (P < .01) and higher 6-month MCS than their counterparts in ST (P = .01). YG led to greater benefit finding than ST and WL across the follow-up (P = .01). Three-month benefit finding partially mediated the effect of YG on 6-month PCS. Posttraumatic stress symptoms and cortisol slope did not mediate treatment effect on QOL. Conclusion Yoga may provide the greatest mental-health-related QOL benefits for those experiencing pre-radiotherapy sleep disturbance and depressive symptoms. Yoga may improve physical-health-related QOL by increasing ability to find benefit in the cancer experience.