Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS), a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ) complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone₁₀ was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol₁₀, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone₁₀ and a new stabilized formulation of ubiquinol₁₀ on the disease course of SOD1^G93A transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally) started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ₁₀ were significantly increased by both treatments (from <0.20 to 3.0–3.4 µg/mL), no effect was found on the disease progression and survival of SOD1^G93A mice. The levels of CoQ₁₀ in the brain and spinal cord of ubiquinone₁₀- or ubiquinol₁₀-treated mice were only slightly higher (≤10%) than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ_9/10 in the plasma, brain and spinal cord of symptomatic SOD1^G93A mice, in comparison with age-matched SOD1^WT. Levels of ubiquinol_9/10, but not ubiquinone_9/10, were significantly higher in the CNS, but not in plasma, of SOD1^G93A mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ₁₀ induced by oral treatments in CNS might be not sufficient to provide significant neuroprotection in SOD1^G93A mice.