Radiation-induced oral mucositis (RIOM) is a painful, dose-limiting toxicity in cancer therapy. RIOM was induced by radiation on the left buccal pouch mucosa of Golden Syrian hamsters (n = 8/group). Animals were treated topically with polyphenols (Curcumin or Quercetin) or amino acids/metabolite mixtures (Alanyl-Glutamine or Arginine + Glutamine + β-Hydroxy β-methylbutyric acid (Arg/Gln/HMB)) for over 20 day. Progression of RIOM was assessed using a standard visual scoring six-point scale, for differences in severity of mucositis (score ≥3) (Chi-square analysis) and in the daily group scores (Mann-Whitney rank sum test). Compared to the controls, there was a significant reduction in number of days with severe RIOM (score ≥3) in the treatment groups: Curcumin (50 μg/ml) = 17%; Control = 38.5%, p < 0.001; Quercetin (50 μg/ml) = 27.6% and Quercetin (100 μg/ml) = 25%; Control = 41.3%, p = 0.007 and p = 0.001, respectively; Arg/Gln/HMB (50 mg/ml) = 31.9%; Control = 50.0%, p = 0.040. In addition, Curcumin (50 μg/ml), Quercetin (100 μg/ml) and Arg/Gln/HMB (100 mg/ml) groups had lower mucositis scores (≥3) on at least two consecutive time points over the course of the study than their respective controls. There were no significant group differences in deaths or body weight. This study demonstrates the potential benefits of topical application of either plant polyphenols or amino acid/metabolite mixtures in addressing severity and progression of RIOM.