BACKGROUND: Oral mucositis (OM) is one of the main problems in almost all patients undergoing head and neck radiotherapy (RT). Owning to the antioxidant and anti-inflammatory properties of curcumin, the effect of both oral and topical formulations of curcumin was assessed on radiation-induced OM (ROM) in this study. METHODS: The safety and efficacy of curcumin mouthwash 0.1% (w/v) and curcumin-nanocapsule were evaluated in ameliorating severity and pain/burning associated with OM during RT. The current randomized, placebo-controlled trial was conducted on 37 patients with head and neck cancers. Patients with grades 1 to 3 of ROM were randomized to receive one of the three interventions: curcumin mouthwash (0.1% w/v); Sinacurcumin soft gel containing 40 mg curcuminoids as nano-micelles (SinaCurcumin®40); or placebo mouthwash with a similar transparent appearance to curcumin mouthwash for 1 min three times daily during RT. Study evaluations were conducted at baseline and weekly thereafter for up to 3 weeks using the Numeric rating scale (NRS) and world health organization (WHO) scale. RESULTS: Among the 45 patients randomized, 37 (mean (SD) age of 53.36 (15.99) years; 14 [37.8%] women) completed the treatment according to the protocol. Patients treated with either oral or topical curcumin showed a significantly reduced severity and burning related to OM during the first 3 weeks after administration (P-Value < 0.001) as compared with the placebo. At study termination, more than 33% of subjects utilizing curcumin mouthwash and 15% of patients utilizing curcumin-nanocapsule remained ulcer free while all of the placebo-receiving subjects had OM. The reduction of NRS and WHO scale between curcumin groups was comparable without significant differences. CONCLUSION: Both curcumin mouthwash and nanocapsule were effective, safe, and well-tolerated in the treatment of radiation-induced OM. Higher doses of curcumin and larger sample sizes can be used for further investigation in future studies. TRIAL REGISTRATION: https://irct.ir/ IRCT20190810044500N17 (13/08/2021).