Background and objectives Radiation-induced mucositis (RIOM) is one of the most common side effects from head and neck radiotherapy. Several reagents have been introduced to manage the symptom; however, there is still a limited number of effective reagents. Herbal mouthwashes with payayor (Clinacanthus nutans Lindau) and fingerroot (Boesenbergia rotunda) were tested their efficacies in preventing and reducing severity of RIOM in comparison with normal saline with sodium bicarbonate. Methods One hundred twenty patients with head and neck cancer undergoing radiotherapy participated in the study and were randomly assigned into three treatment groups using block randomization method. The participants were assigned one of the three mouthwashes for use throughout their radiotherapy course and were assessed for their mucositis scores from week one to six into their radiotherapy course as well as at one-month follow-up. Body mass index was also measured for comparison of nutritional status. Results The two mouthwashes were similarly effective in prophylaxis of RIOM in term of severity. The averaged mucositis scores were less than two for all groups. For the onset of RIOM, both herbal mouthwashes could slightly delay the symptom but not statistically significant. Patients’ body mass index across the three treatment groups was also comparable. The patients were largely satisfied with all the mouthwashes with no clear preference on any of them. Conclusions Prophylactic treatment of RIOM using herbal mouthwashes could substitute the current standard of normal saline with bicarbonate. A different formulation of the two herbs could potentially improve the prophylactic outcome. Trial Registration No NCT03359187.