Background: Fatigue is a common side effect in cancer patients undergoing radiation therapy (RT). Radiation-induced fatigue affects the quality of life, but there is no definitive treatment option. In this study, the weight-loaded forced swim test was performed to assess the effect of coenzyme Q10 (CoQ10) on radiation-induced fatigue. Materials and Methods: A total of 60 rats were divided randomly and equally into four groups: No swim, No RT, RT + placebo, or RT + CoQ10. The No swim, No RT, and RT + placebo groups received 1 mL of soybean oil daily for 14 days. The RT + CoQ10 group received 100 mg/kg of CoQ10 in soybean oil at the same times. Both RT groups were irradiated with 10 Gy on the 14th day of treatment. The swim test with sinkers weighing 10% of body weight was performed 24 h later in all animals except the No swim group. Results: The level of blood urea nitrogen (BUN) was significantly lower in the No swim than the other groups. The BUN level of the No RT group was significantly decreased compared with the RT + placebo group, but it did not differ from the RT + CoQ10 group. Swimming times to complete exhaustion were significantly longer in the No RT and RT + CoQ10 groups compared to the RT + placebo group (99.4, 105.9, and 75.7 s, respectively) (P<0.001). Conclusion: Supplementation with CoQ10 can prevent the decrease in endurance capacity caused by radiation.