Objectives <p>Direct-acting antivirals (DAAs) have revolutionized hepatitis C (HCV) treatment, yet their high cost necessitates rigorous economic evaluation. Glecaprevir/Pibrentasvir (GLE/PIB) and Grazoprevir/Elbasvir (GZR/EBR) are two key, highly effective DAA regimens, but their comparative cost-effectiveness across different healthcare settings remains unclear. This study aims to systematically review and qualitatively synthesize the economic evidence for GLE/PIB and GZR/EBR, comparing them with each other and other relevant HCV treatments.</p> Methods <p>A systematic review was conducted by searching PubMed, Scopus, Embase, Science Direct, and the Cochrane Library for full economic evaluation studies published up to September 2025. The quality of included studies was assessed using the CHEERS checklist. Due to significant heterogeneity in study contexts, populations, and methodologies, a qualitative narrative synthesis was performed, and quantitative pooling of economic outcomes was avoided.</p> Results <p>A total of 20 economic evaluation studies were included. Both GLE/PIB and GZR/EBR were consistently found to be cost-effective or dominant strategies when compared to older interferon-based therapies. However, the five head-to-head studies comparing GLE/PIB and GZR/EBR yielded conflicting results: GLE/PIB was the economically preferred option in settings like Japan and Brazil, whereas GZR/EBR was favored in analyses from China and Hong Kong. This variability appears to be primarily driven by differences in local drug acquisition prices.</p> Conclusion <p>Neither GLE/PIB nor GZR/EBR can be considered universally more cost-effective than the other. Both regimens represent valuable advancements over previous standards of care, but the optimal economic choice between them is highly context-dependent. These findings underscore the necessity of using local, setting-specific economic evaluations to inform clinical guidelines and reimbursement policies.</p>