Background: Around 50 million people worldwide have Hepatitis C virus (HCV) infection, suggesting its significant public health impact. Direct-acting antiviral agents (DAAs) have revolutionized HCV treatment, resulting in high sustained virological response rates (SVR). A small but considerable minority of patients fail to achieve SVR, which is a major issue. This issue is especially important when non-structural protein 5A (NS5A) inhibitor-based therapies fail. This requires the best management practices. Objectives: This review article aimed to outline the current recommendations for retreatment of HCV infection after prior unsuccessful DAAs therapy. Methods: The terms Hepatitis C virus, Direct-acting antivirals and DAA treatment failure were used to search PubMed, Science direct and Google scholar. Additionally, the writers culled references from the pertinent literature, identifying and included just the most current or comprehensive study out of all the found studies and reviews. The search for literature was limited to English language works. Dissertations, oral presentations, conference papers, unpublished articles, and abstracts from smaller scientific investigations were excluded. Conclusion: The 12-week treatment plan of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is the main approach for treating instances of HCV that did not achieve SVR after previous treatments containing NS5A inhibitors and/or protease inhibitors. Nevertheless, for individuals with liver cirrhosis and genotype 3, the inclusion of ribavirin (RBV) or prolonging the duration of treatment to 24 weeks could potentially be advantageous. On the other hand, individuals who have previously undergone repeated DAA therapy may need to undergo retreatment with either a combination of SOF/VEL/VOX or a combination of sofosbuvir, glecaprevir, and pibrentasvir together with ribavirin for a duration of 16-24 weeks. Additionally, persons suffering from decompensated liver cirrhosis should have a second round of treatment using the SOF/VEL/RBV combination for a duration of 24 weeks. The multi-targeted DAA treatment strategy represents an effective anti-HCV rescue therapy for post DAAs treatment failures, although a minority of cases will remain in need for more advanced therapeutic options.