Hypothesis. Withania somnifera is an herb with antioxidant, anti-inflammatory, anticancer, antistress, and adaptogenic properties. Previous studies have shown its antistress effects in animals. Traditional Indian medicine has used it for centuries to alleviate fatigue and improve general well-being. Methods. This is an open-label prospective nonrandomized comparative trial on 100 patients with breast cancer in all stages undergoing either a combination of chemotherapy with oral Withania somnifera or chemotherapy alone. The chemotherapy regimens were either taxotere, adriamycin, and cyclophosphamide or 5-fluorouracil, epirubicin, and cyclophosphamide. Withania somnifera root extract was administered to patients in the study group at a dose of 2 g every 8 hours, throughout the course of chemotherapy. The quality-of-life and fatigue scores were evaluated before, during, and on the last cycles of chemotherapy using the EORTC QLQ-C30 (Version 3), Piper Fatigue Scale (PFS), and Schwartz Cancer Fatigue Scale (SCFS-6). Results. The median age distributions in the study and control arm were 51 years (range = 36-70) and 50.5 years (range = 32-71), respectively. The majority (77%) of patients had stage II and III disease. Patients in the control arm experienced statistically significant higher estimated marginal means of fatigue score compared with the study group ( P < .001 PFS, P < .003 SCFS-6). Furthermore, various symptom scales of the EORTC QLQ-C30 were statistically significant in 7 out of 18 symptoms in the intervention group compared with the control group ( P < .001). The 24-month overall survival for all stages in study and control group patients were 72% versus 56%, respectively; however, the result was not significant ( P = .176), at a median follow-up duration of 26 months. Conclusions. Withania somnifera has potential against cancer-related fatigue, in addition to improving the quality of life. However, further study with a larger sample size in a randomized trial is warranted to validate our findings.