Objective In this study, we investigated the use of direct-acting antivirals (DAAs), medical expenses and clinical outcomes since the initiation of national health insurance coverage in Taiwan. Methods This was a retrospective observational study. We obtained claims data from Taiwan’s National Health Insurance Research Database in 2017. Patients diagnosed with hepatitis C with at least two physician visits or one hospitalization were included in the study. Cases were divided into three groups based on the treatment type: traditional treatment (interferon, INF), new drug treatment (DAA) and INF-experienced (INF followed by DAA). We compared the distributions of various cases based on individual demographic variables, hospital type and comorbidities. Trends in medical expenses by treatment type were estimated. We also analyzed clinical outcomes, including rehospitalization and liver function disorders, using a survival analysis method. Results Among patients with hepatitis C, the DAA group had a significantly higher proportion of females, a higher mean age and greater disease severity than the INF group. The growth rate of medical expenses was significantly lower in the DAA group. In addition, compared to the INF group, the DAA group and INF-experienced group had significantly lower rehospitalization rates, and the DAA group had a significantly lower risk of liver function disorders. Furthermore, the longer a patient received any form of treatment, the lower was their chance of rehospitalization and liver function disorders. Conclusions In conclusion, our results confirmed that insurance coverage of DAAs led to better clinical outcomes than INF, and this may reduce increases in medical expenses and the risks of rehospitalization and liver function disorders. What is known on this topic Interferon for hepatitis C has low efficacy with serious side effects, while the efficacy of new oral drugs (direct-acting antivirals, DAAs) is high. DAAs were approved for listing in Taiwan in December 2013, and they have been covered by National Health Insurance since January 2017. Little is known about DAA-related real-world evidence following the coverage of DAAs in Taiwan, including drug utilization, expenditures and safety. What this study adds This study explored three important issues related to DAAs: drug utilization, medical expenses and clinical outcomes following the insurance coverage by using the National Health Insurance Database. Cases were divided into three groups based on the treatment type: traditional treatment (interferon, INF), new drug treatment (DAA) and INF-experienced (INF followed by DAA). After the adjustment of various personal and hospital factors, the DAA group and INF-experienced group had significantly lower rehospitalization rates, and the DAA group had a significantly lower risk of liver function disorders, compared to the interferon group. There was a lower chance of rehospitalization and lower liver function disorder rates with longer treatment.