Background <p>Radiation-induced oral mucositis (RIOM) is a common and debilitating complication of radiotherapy in oral cancer patients, significantly impairing quality of life and potentially interrupting treatment. This study evaluated the therapeutic efficacy of N-acetylcysteine (NAC) nano-spray in managing RIOM, with particular emphasis on mucositis severity, quality of life, and serum gastrin-17 levels.</p> Materials and methods <p>In this randomized clinical study, 40 oral cancer patients undergoing radiotherapy were allocated in a 1:1 ratio to receive either NAC nano-spray (<i>n</i> = 20) or conventional therapy (<i>n</i> = 20) for six weeks. Mucositis severity was assessed using the World Health Organization (WHO) Oral Mucositis Severity Scale, and quality of life was evaluated using the Oral Health Impact Profile (OHIP-14). Serum gastrin-17 levels were measured before and after treatment.</p> Results <p>Patients treated with NAC nano-spray demonstrated a significant reduction in WHO mucositis grades and significantly improved OHIP-14 scores compared with the control group (<i>p</i> &lt; 0.05). Additionally, a significant increase in serum gastrin-17 levels was observed in the NAC group relative to conventional therapy (<i>p</i> &lt; 0.05). These effects were evident during radiotherapy and at the end of treatment.</p> Conclusions <p>N-acetylcysteine nano-spray appears to be an effective therapeutic option for the management of RIOM, reducing mucositis severity and improving quality of life in oral cancer patients.</p> Trial registration <p>The trial was registered at Clinical Trials .gov on 24/7/2025, registration number: (NCT07082621).</p>