Direct acting antiviral treatment (DAA) has been the standard of care for hepatitis C virus (HCV) infection, but its long-term benefits in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) improvement and hepatic fibrosis assessed by aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 index (FIB-4) scores remain unknown. The purpose of the present study was to assess DAA's long-term benefits, including frequencies of posttreatment week 96 ALT/AST < 30 (males)/19 (females) (<30/19), improvement of APRI and FIB-4 scores, and the associated factors. This was a single-center, retrospective study on 157 patients with HCV with DAA-mediated sustained virological response (SVR) 12. At posttreatment week (post-Rx wk) 96, 75.4% had ALT < 30/19; 62.7%, AST < 30/19; and 60.1%, both ALT/AST < 30/19. ALT/AST < 30/19 at post-Rx wk 96 was associated with ALT/AST < 30/19 at post-Rx wk 12 (p=0.026), independently of Child-Turcotte-Pugh < 6 (p=0.862), platelets ≤ 120 × 109 /L (p=0.343). Improvement rates of APRI < 0.5 and FIB-4 < 1.45 from baseline to post-Rx wk 96 were from 30.9% to 80.5%, and from 23% to 37.8%, respectively. Both APRI and FIB-4 improvement was associated with both ALT/AST < 30 (males)/19 (females) at post-Rx wk 12 (p=0.012 and 0.011, respectively). Conclusion: The present study showed that DAA-mediated SVR12 in patients with HCV resulted in (1) high and durable rates of ALT (75.4%), AST (62.7%), and both ALT/AST (60.1%) < 30/19, and (2) high rates of APRI < 0.5 (80.5%) and FIB-4 < 1.45 (37.8%) at post-Rx wk 96, demonstrated clinical value of ALT/AST < 30/19 and excellent long-term outcomes of DAA-mediated SVR12 in these patients.