Purpose <p>Head and neck cancer (HNC) patients undergoing radiation therapy (RT) often experience mask anxiety due to the use of thermoplastic masks for immobilization. This study evaluated the effectiveness of a combined music therapy and relaxation-visualization intervention in reducing mask anxiety among HNC patients receiving RT at a tertiary care super-specialty oncology hospital in central India.</p> Methods <p>A total of 216 HNC patients scheduled for RT were randomized into either the intervention group (<i>N</i> = 108) or the control group (<i>N = </i>108). Mask anxiety was assessed using a modified distress thermometer (MDT) at baseline and after five RT sessions. Participants in the intervention group listened to pre-recorded soft instrumental, non-lyrical music and practiced a guided relaxation-visualization technique during their first five RT sessions. The control group received standard medical care.</p> Results <p>Of the enrolled participants, 208 were included in the final statistical analysis (intervention group: <i>N = </i>100; control group: <i>N</i> = 108). At the end of five RT sessions, the intervention group showed a statistically significant reduction in mask anxiety scores [median (IQR): 2 (2)] compared to the control group [median (IQR): 6 (1)], with <i>p</i> &lt; 0.001. No adverse events were reported. However, four participants discontinued the intervention, citing distracting thoughts and difficulty concentrating.</p> Conclusion <p>The findings support the potential of music therapy combined with relaxation-visualization as an effective non-pharmacological intervention to alleviate mask anxiety in HNC patients undergoing RT. Integrating such complementary strategies into routine oncology practice may enhance emotional well-being, promote treatment adherence, and improve overall treatment outcomes. Further large-scale validation is warranted.</p> Registration number of the clinical trial <p>CTRI/2023/02/049409 (Registered prospectively on 02/02/2023).</p>