Next-generation sequencing (NGS) can enable a more effective response to a wide range of communicable disease threats, such as influenza, which is one of the leading causes of human morbidity and mortality worldwide. After vaccination, antivirals are the second line of defense against influenza. The use of currently available antivirals can lead to antiviral resistance mutations in the entire influenza genome. Therefore, the methods to detect these mutations should be developed and implemented. In this Opinion, we assess how NGS could be implemented to detect drug resistance mutations in clinical influenza virus isolates.