Background: Patients undergoing radiotherapy (RT) for head and neck tumors are prone to experiencing nutritional and psychological issues as a result of adverse events to the treatment, which may ultimately lead to radiotherapy interruption (RTI). We conducted a prospective, randomized controlled trial to assess the effect of nurse-led multi-disciplinary treatment (MDT) interventions, incorporating psychological and nutritional interventions, on RTI rates and quality of life (QoL) among patients undergoing RT for head and neck tumors. Methods: Patients with head and neck cancer undergoing RT at West China Hospital, Sichuan University were enrolled. Eligible patients were randomly assigned in a 1:1 ratio to receive either the standard oncology care (standard group) or the nurse-led, whole-course MDT care (MDT group). The MDT care included nutritional and psychological interventions provided by a team of a radiotherapist, an oncology specialty nurse, a dietitian, a psychotherapist and a rehabilitation therapist. The primary end point was RTI rate in the per-protocol set (PPS). Patients’ QoL was assessed using the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires. Nutritional status was assessed using NRS 2002 and PG-SGA, and psychological status was assessed using DT, PHQ-9 and HADS. Results: A total of 233 patients were enrolled in the study. At the final follow-up, 112 patients in the standard group and 114 patients in the MDT group completed all follow-up assessments. The RTI rate in the MDT group was significantly lower than that in the standard group (MDT vs. standard: 11.4% vs. 25.9%, P= 0.005). Differences in QoL among patients favored MDT care over standard care, particularly in emotional function, GHS, fatigue, and insomnia. Baseline patients’ nutritional and psychological status were similar between two groups. From mid-RT to 6 months after RT, the nutritional and psychological status of patients in the MDT group improved at certain follow-up points compared with the control group. The rehospitalization rate in the MDT group was significantly lower than that of control group (MDT vs. standard: 7.9% vs. 18.8%, P= 0.016). Conclusions: Nurse-led MDT interventions effectively reduces RTI, improves nutritional status of patients, and alleviates their psychological burden, making it a worthy approach for dissemination in developing countries. Clinical trial information: NCT05828004.