Huntington’s disease (HD) is one of the human neurodegenerative diseases for which there is no effective treatment. Therefore, there is a strong demand for a novel neuroprotective agent that can alleviate its course. Fullerene derivatives are considered to be such agents; however, they need to be comprehensively investigated in model organisms. In this work, neuroprotective activity of C₆₀(OH)₃₀ and C₁₂₀O(OH)₄₄ fullerenols was analyzed for the first time in a Drosophila transgenic model of HD. Lifespan, behavior, oxidative stress level and age-related neurodegeneration were assessed in flies with the pathogenic Huntingtin protein expression in nerve cells. Feed supplementation with hydroxylated C₆₀ fullerene and C₁₂₀O dimer oxide molecules was shown to diminish the oxidative stress level and neurodegenerative processes in the flies’ brains. Thus, fullerenes displayed neuroprotective activity in this model.