Influenza viruses (IV) continue to pose an imminent threat to human welfare. Yearly re-occurring seasonal epidemic outbreaks and pandemics with high mortality can occur. Besides vaccination against a limited number of viral strains only a few antiviral drugs are available, which are losing their effectiveness as more and more IV strains become resistant. Thus, new antiviral approaches that omit IV resistance are urgently needed. Here, the dependency on the cellular Raf/MEK/ERK signaling pathway for IV replication opens a new perspective. In consequence, we studied the antiviral potential of the MEK inhibitor Cl-1040 (PD184352). We show that Cl-1040 significantly reduces virus titers in vitro via retention of viral RNP complexes in the cell nucleus. Furthermore, Cl-1040 is effective against a broad range of IV strains, including highly pathogenic avian IV, as well as against a Tamiflu?-resistant IV strain. Using a mouse model, we demonstrate that Cl-1040 can reduce IV lung titers in vivo. Importantly, the treatment window for Cl-1040 expands up to 48 h post infection when Tamiflu? treatment has no effect. In conclusion, Cl-1040 offers an interesting perspective for anti-IV approaches.