Purpose: Evaluating the influence of coenzyme Q10 (CoQ10) supplementation as a novel therapeutic strategy in the prevention of radiation-induced oral mucositis (RIOM). Methods: The study has been conducted on 39 rats; 13 of them served as the control group (group I). The remaining rats have been subjected to radiation exposure of the neck and head region with or without oral administration of CoQ10 ( group II and group III) . The oral mucositis index (OMI) was scored, pro-inflammatory markers Tumor Necrosis Factor-alpha (TNF-α)] and interleukin-1 beta (IL-1β) and superoxide dismutase (SOD) were evaluated. Results: The oral mucositis scores (0–5 points), for radiation-exposed groups significantly increased one and two weeks post-radiation (Group II: 2.8 ± 0.9 and 4.5 ± 0.7; Group III: 1.8 ± 1.4 and 3 ± 2.2), whereas Group I remained scoreless at 0, as proven by Friedman’s test p < 0.001 w = 0.526 and 0.096, respectively. Regarding the hematological assessment, concentrations of Tumor Necrosis Factor-alpha and interleukin-1 beta weresignificantly the highest in Group II (107.5 ± 2.6 and 63.4 ± 2.6 pg/ml), lower in Group III (92.7 ± 1.3 and 42.8 ± 1.3), and the lowest in Group I (64.2 ± 2.9 and 25.7 ± 0.7) with a high effect size (η²=0.984, 0.989). The SOD activity presented an opposite variation, as it was greatestin the III (2.87 ± 0.08 µ/ml) and smallest in the II (0.96 ± 0.03), with η² = 0.993. Conclusion: CoQ10 can ameliorate oral mucositis induced by radiation through its anti-inflammatory and antioxidant effects.