Abstract Purpose Knowledge of caregivers’ burden and fatigue before and after patients’ treatment for locally advanced head and neck cancer is scarce. Therefore, we aimed to explore caregivers’ fatigue and burden in relation to patients’ fatigue, distress, and quality of life. Methods For caregivers, burden and fatigue were assessed. For patients, fatigue severity, distress, and health-related quality of life (HRQoL) were assessed. Measurements were conducted prior to treatment, 1 week, and 3 months after chemoradiotherapy. Results Caregivers’ burden and fatigue followed patients’ high peak in distress, fatigue, and diminished HRQoL as a consequence of treatment. Caregivers’ baseline fatigue was a predictor for fatigue after chemoradiotherapy. Female spouses with higher baseline levels offatigue and burden and caring for patients with lower levels ofHRQoL seem risk factors for burden after chemoradiotherapy. Conclusions Attention should be paid to caregivers’ burden and fatigue before starting patients’ intense treatment with chemoradiotherapy, as both burden and fatigue before starting treatment may contribute to burden and fatigue after chemoradiotherapy.