Seasonal influenza viruses cause approximately 3-5 million cases of illness and 250,000-500,000 deaths globally annually, burdening the healthcare system. Currently, the best intervention against seasonal influenza is the annual vaccine, which protects against Influenza Type A subtypes H1N1, H3N2, and Type B viruses, all of which are endemic in humans. However, vaccine strains must be decided one year before the season, as the dominant seasonal strains may change year to year, which can lead to reduced efficacy. Typically, the first line of post-exposure defense for severe or complicated influenza infection is antivirals such as Oseltamivir. However, influenza quickly gains resistance against antivirals, limiting their value for sustained use during outbreaks. By utilizing DiscoveryProbe pre-aliquoted drug panels from ApexBio against a seasonal strain of H1N1 influenza, I aimed to discover novel antivirals to identify more options for emergency antiviral use in the case of future severe cases or seasonal IAV infection. In vitro screening of FDA-approved drug panel from ApexBio identified two compounds that provided protection against A/Canada/RV733/2007 H1N1 with limited cytotoxicity in MDCK and A549 cells. Screening of the Natural Product library panel from ApexBio identified 12 compounds that provided protection with limited cytotoxicity. Testing these compounds against seasonal and pandemic H1N1, A/Hong Kong/1/68 H3N2, a recombinant VSV, and a seasonal Rhinovirus showed that several of the compounds were effective against a wide range of infectious agents. Testing in both MDCK and A549 cell lines showed that the effectiveness of the compounds occasionally differed between cell lines. Further characterization using immunofluorescent assays to track viral proteins during infection in the presence of the compounds of interest showed that sodium aescinate, calycosin-7-glucoside, oridonin, dioscin, and kinetin reduced viral protein fluorescence 24 hours post-infection. Hemagglutination inhibition assays, attachment and penetration blockades, and attachment immunofluorescent assays suggested that oridonin and dioscin may be inhibiting on IAV attachment, while sodium aescinate and calycosin-7-glucoside may be having a negative effect on IAV penetration. These novel antivirals could provide new possibilities for treatment of influenza infections, and provide additional options for the management of inevitable future IAV outbreaks.