Influenza viruses pose a significant threat due to annual epidemics and pandemic potential. Resistance to current antivirals underscores the need for new drugs and strategies to prevent its emergence. We previously developed two novel HA-targeting compounds (CD-6′SLN and CD-SA) with demonstrated efficacy against influenza A and B strains. Here, we compared their resistance barrier to that of FDA-approved oseltamivir (OS) and baloxavir marboxil (BXM). We established a resistance testing assay in human airway epithelia (HAE) and in mice. We also evaluated the impact of combination therapies on resistance emergence. In HAE, highly reduced inhibition (HRI) by CD-6′SLN and CD-SA occurred within 2 and 4 weeks respectively without fitness loss, while reduced inhibition (RI) by baloxavir acid (BXA) emerged within 4 weeks. No reduction of susceptibility to OS was observed in the same time frame. Of note, emergence of RI by CD-SA was not delayed in BXA/CD-SA co-treatment, and slightly reduced upon OS/CD-SA co-treatment. In mice, RI by CD-SA was observed after 8 passages in one of three mice treated with OS/CD-SA, but not in mice with single therapies. This study demonstrates that (1) HAE represents a relevant model to detect emergence of resistance and (2) HA-targeting compounds are prone to induce resistance followed by BXA and OS. Importantly, combination of clinically available antivirals and HA-targeting compounds did not prevent the emergence of variants with HA substitutions. Additional research is needed to develop anti-influenza antivirals with high resistance barrier and compounds should be tested in HAE before moving to animal experimentation.