We focused on evaluating oxidative stress as a major mechanism of cell damage in patients with COVID-19 infection by simultaneously assessing standard oxidative stress biomarkers in vivo-for the very first time in this specific combination-alongside typical clinical biomarkers of inflammation. Standard biomarkers were used to evaluate the oxidative stress status and antioxidant activity in the blood plasma of COVID-19 patients and healthy controls. These included TBARSs (Thiobarbituric Acid-Reactive Substances), SOD (Super Oxide Dismutase), CAT (catalase), GRA (glutathione reductase) activities, and AOC (antioxidant capacity). All clinical inflammation data confirmed a highly activated immune response in the tested COVID-19 patients: WBCs (white blood cells) were increased by nearly 100%, LYMs (lymphocytes) increased by ~30%, CRP (C-reactive protein) rose by over 2200%, and the ESR (erythrocyte sedimentation rate) increased by ~320% compared to established maximum control levels. The results confirmed that the infection involved a free-radical-mediated damage mechanism: TBARS levels increased almost 3-fold, the AOC decreased more than 4-fold, SOD was increased nearly 5-fold, CAT was increased by 1.4 times, and GRA was suppressed by 2.5 times. COVID-19 was associated with oxidative stress and suppressed antioxidant activity. All these changes contribute to the severity of the disease, complications, and mortality in COVID-19 patients.