The study evaluated the effects of two direct-acting antiviral regimens – Glecaprevir/Pibrentasvir (G/P) and Sofosbuvir/Velpatasvir (S/V) – on metabolic and inflammatory biomarkers in 70 patients with hepatitis C and comorbidities such as hypertension or type 2 diabetes. Chronic HCV infection causes metabolic disturbances including glucose intolerance, lipid dysregulation and inflammation, which accelerates liver fibrosis. Patients were stratified by treatment type, fibrosis stage (F0–F4), and baseline cholesterol; liver stiffness was measured by FibroScan and biomarkers by the Luminex FlexMAP 3D system. Both regimens significantly changed biomarkers: they increased ANGPTL6, FGF-19, ghrelin, total cholesterol, HDL and non-HDL, while decreasing FABP-1 and MCP-1, indicating a reduction in inflammation and lipid stress. Patients with lower baseline cholesterol and S/V had stronger effects in advanced fibrosis, while G/P showed significant anti-inflammatory effects in early fibrosis. Thus, DAA therapy alters metabolic and inflammatory biomarkers specifically according to the mode and stage of fibrosis, with S/V providing broader metabolic benefits in advanced disease and G/P stronger anti-inflammatory responses earlier.