Purpose: To evaluate systemic oxidative stress by comparing serum 8-hydroxy-2′-deoxyguanosine (8-OHdG), coenzyme Q10 (CoQ10), malondialdehyde (MDA), and 25-hydroxyvitamin D (25(OH)D) levels between primary open-angle glaucoma (POAG) patients and healthy controls. Methods: This prospective case-control study included 37 POAG patients and 35 age-matched controls. Serum levels were measured via enzyme-linked immunosorbent assay. Nonparametric tests (Mann-Whitney U-test and Spearman correlations) and multivariate linear regression adjusting for age and sex were used. Results: POAG patients showed significantly higher MDA (3.01 vs. 2.46 nmol/mL, p = 0.021) and 8-OHdG (9.34 vs. 6.52 ng/mL, p < 0.001), but lower CoQ10 (7.28 vs. 8.98 ng/mL, p < 0.001) and 25(OH)D (15.02 vs. 17.45 ng/mL, p = 0.013). MDA and 8-OHdG showed a strong positive correlation (rho = 0.855, p < 0.001). CoQ10 and 8-OHdG showed a moderate positive correlation (rho = 0.466, p = 0.004). No significant correlation was found between 25(OH)D and 8-OHdG (rho = –0.118, p = 0.488). After adjusting for age and sex, POAG remained independently associated with lower CoQ10 (p < 0.001). No oxidative marker correlated with intraocular pressure, visual field mean deviation, or retinal nerve fiber layer thickness in POAG patients (all p > 0.05). Conclusions POAG patients exhibit systemic oxidative imbalance with elevated oxidative damage and reduced antioxidant capacity. The positive CoQ10–8-OHdG correlation may suggest a compensatory relationship. This imbalance is associated with POAG but does not correlate with clinical severity cross-sectionally, suggesting it reflects a systemic disease component rather than a direct severity marker.