Objectives <p>More than 75% of high-risk individuals experience oral mucositis as a side effect of head, neck, and oral radiotherapy and chemotherapy. The chemical N-acetyl cysteine (NAC) has substantial antioxidant, anti-inflammatory, and antibacterial properties. The goal of this study was to determine the effectiveness of NAC mouthwash in preventing chemotherapy-induced oral mucositis.</p> Materials and methods <p>In the current randomized, double-blind controlled trial, 68 patients were randomly divided into two groups (34 patients in the intervention group and 34 patients in the control group).</p> <p>The recommended therapeutic dose was 1.25% NAC mouthwash. In this 14-day study, the patients were instructed to use the NAC mouthwash twice daily (15 milliliters each dose). The oral mucosa was evaluated on days 1,7, and 14 following the initiation of chemotherapy and the score was documented based on observation.</p> Results <p>On the 7^th day, the severity of mucositis was significantly greater in the control group than in the intervention group (<i>P</i> &lt; 0.001). However, this difference was not significant on day 1 (<i>P</i> = 0.459) and day 14 (<i>P</i> = 0.999) of the study. Also on 7th day, the incidence of mucositis was significantly lower in patients receiving N-acetyl cysteine than patients receiving placebo. However, no significant difference was observed on day 1 (<i>P</i> = 0.144) and day 14 (<i>P</i> = 0.999) of the study.</p> Conclusion <p>According to the results, NAC mouthwash leads to a decrease in the severity of mucositis caused by chemotherapy. It seems that it can be effective as a treatment and preventive medicine for mucositis.</p> Clinical relevance <p>According to the findings, NAC mouthwash lessens mucositis severity and may help to prevent its onset.</p>