Primary mitochondrial diseases (PMD) are rare disorders with limited therapeutic options. Coenzyme Q10 (CoQ10) supplementation is widely used, although formulation differences can affect absorption and efficacy. This open-label pilot feasibility trial evaluated a food for special medical purposes (FSMP) containing high-dose CoQ10 (250 mg per capsule) in patients with PMD. Ten patients (mean age: 55.5 ± 8.6 years) were enrolled. Serum/plasma biomarkers, including CoQ10, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), ferric-reducing antioxidant power (FRAP), total sulfhydryl groups (t-SH), and advanced oxidation protein products (AOPP), were assessed at baseline (T0, after ≥30 days of conventional ubidecarenone) and after 30 days of FSMP administration (T1). Fatigue severity scale (FSS) and 5-times sit-to-stand test (5xSST) were evaluated at both timepoints. FSMP was administered at 250 or 500 mg/day. Twenty sex- and age-matched healthy controls were included for CoQ10 comparison. Absolute CoQ10 concentrations remained stable overall at T1, with all patients maintaining levels above 390 ng/mL (100% vs. 60% at T0), although concentrations remained lower than in healthy controls (p < 0.01). Dose-normalized CoQ10 exposure was significantly higher with FSMP versus conventional ubidecarenone (p < 0.001, Cohen’s d = 7.31). FGF21, GDF15, AOPP, and t-SH remained unchanged, whereas FRAP increased at T1 (p < 0.01). No significant changes were observed in 5xSST and FSS. Exploratory analyses indicated inter-individual variability in functional responses. FSMP was associated with higher dose-normalized systemic CoQ10 exposure, more consistent circulating CoQ10, and increased FRAP levels. Its simplified dosing regimen may support long-term adherence. Larger studies are warranted to validate these preliminary findings.