Background &amp; objectives <p>Genomic diversity of Hepatitis C Virus (HCV), accessibility and long-term influence of Direct Acting Antiviral (DAA) treatment remain underexplored among HCV-infected chronic liver disease (CLD) patients in the real world. This retrospective study addressed the inadequacy of assessing the effectiveness of DAA and identify genotype-specific variations in treatment response in the context of HCV epidemiology. Additionally, real-world treatment challenges encountered during the COVID-19 pandemic and the transitional phase of implementing the National Viral Hepatitis Control Program (NVHCP) guidelines have also been addressed.</p> Methods <p>This retrospective study included 254 CLD patients from November 2017 and February 2020 to assess the effectiveness of DAA and long-term treatment outcomes among CLD patients.</p> Results <p>HCV viremia was observed in 58.26% (<i>n</i> = 148) patients. Patients aged 52–59 years with a history of blood transfusions exhibited a higher prevalence of active HCV infection. Two major genotypes (GT) - GT1 and GT3, and seven subtypes with few new subtypes were identified. SVR₂₄ was achieved in 89.6% of patients receiving sofosbuvir (SOF) + daclatasvir (DCV) or SOF/ledipasvir (LDV) drug regimens. For individuals who failed to reach SVR₂₄ (<i>n</i> = 13), a modified regimen (SOF + Velpatasvir (VEL) + ribavirin (Riba) for 6 months) was given and the success rate was 92.31%. GT-1a and GT-1b showed better treatment response, whereas GT-3b had a lower treatment response. Among 77 SVR₂₄ achieved patients, 57.14% were cirrhotic and 42.86% were non-cirrhotic at the start of the therapy.</p> Interpretation &amp; conclusion <p>This study highlights genotype-specific variations in treatment response, with GT-3b exhibiting lower treatment response which highlights the need to decipher the reasons behind treatment failure for future therapeutic management.</p>