PURPOSE: Fatigue and anxiety are common and significant symptoms reported by cancer patients. Few studies have examined the trajectory of multidimensional fatigue and anxiety, the relationships between them and with quality of life. METHODS: Breast cancer patients (n = 580) from community oncology clinics and age-matched controls (n = 364) completed fatigue and anxiety questionnaires prior to chemotherapy (A1), at chemotherapy completion (A2), and six months post-chemotherapy (A3). Linear mixed models (LMM) compared trajectories of fatigue /anxiety over time in patients and controls and estimated their relationship with quality of life. Models adjusted for age, education, race, BMI, marital status, menopausal status, and sleep symptoms. RESULTS: Patients reported greater fatigue and anxiety compared to controls at all time points (p's < 0.001, 35% clinically meaningful anxiety at baseline). From A1 to A2 patients experienced a significant increase in fatigue (β = 8.3 95%CI 6.6,10.0) which returned to A1 values at A3 but remained greater than controls' (p < 0.001). General, mental, and physical fatigue subscales increased from A1 to A2 remaining significantly higher than A1 at A3 (p < 0.001). Anxiety improved over time (A1 to A3 β =  - 4.3 95%CI -2.6,-3.3) but remained higher than controls at A3 (p < 0.001). Among patients, fatigue and anxiety significantly predicted one another and quality of life. Menopausal status, higher BMI, mastectomy, and sleep problems also significantly predicted change in fatigue. CONCLUSION: Breast cancer patients experience significant fatigue and anxiety up to six months post-chemotherapy that is associated with worse quality of life. Future interventions should simultaneously address anxiety and fatigue, focusing on mental and physical fatigue subdomains.