Influenza virus is one of the most important and dreadful viruses worldwide. It causes each year annual epidemics that have a strong socio-economic impact. In addition to seasonal epidemics, the virus is able to cause also dangerous pandemics, due to its broad host reservoir and the ability to cross inter-species barriers, giving rise to new reassorted strains. Influenza virus possesses a high genetic variability, which allows for the acquisition of resistance mutations to antiviral treatments. As a result, traditional antiviral therapies based on single medications can lead to the quick emergence and spread of resistant strains. Recent studies have shown that combined antiviral therapies, targeting different components of the virus or mechanisms of viral replication, could not only increase the efficiency of the cures, but also reduce the probability of resistance emergence. The aim of this study is to assess in vitro the genetic barrier to antiviral resistance of a laboratory adapted strain of H1N1 Influenza virus, against single and combined antiviral treatments. We tested both newly developed and traditional antivirals in combination with human interferon lambda, a host innate antiviral molecule. Among other findings we report that the co-administration of interferon lambda delays the emergence of resistance to Oseltamivir, a broadly used antiviral, against which Influenza resistant strain already emerged around 20 years ago. Our results suggest a possible application of interferon lambda in combination with other drugs to treat Influenza as well as other respiratory viral infections.