Glutathione (GSH) is a potent antioxidant and anti-inflammatory, proven effective in reducing treatment duration, prescribed doses, and hospitalization for several diseases. This study assessed the therapeutic response of chronic obstructive pulmonary disease (COPD) patients by measuring oxidative superoxide dismutase (SOD3), glutathione peroxidase 1 (GPX1), and inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-α) and Interleukin-8 (IL-8) after sublingual administration of glutathione supplements. A cohort of 50 COPD individuals was involved and divided into two groups of 25 each. The first group received conventional therapy involving the administration of formoterol fumarate (12 µg inhaler) twice daily. The second group received the conventional treatment alongside sublingual glutathione (300 mg twice daily) for two months. The levels of serum IL-8, TNF-α, SOD3, and GPX1 were assessed before therapy, as well as at one and two months after treatment, in both cohorts. Both groups exhibited a notable reduction in the inflammatory mediators IL-8 and TNF-α when compared to their respective pre-treatment levels (P value <0.05). However, it is worth noting that the observed difference between the groups was not statistically significant (P value >0.05). The levels of SOD3 and GPX1 exhibited a substantial rise in both groups; however, they were found to be greater in group 2 compared to group 1 (P value >0.05). The administration of glutathione resulted in enhanced levels of antioxidant biomarkers among individuals diagnosed with COPD, accompanied by a minor and statistically insignificant decrease in the levels of the anti-inflammatory mediators IL-8 and TNF-alpha.