Highly pathogenic avian influenza A viruses (HPAIV) pose a significant threat to both animal and human health. These viruses have the potential to cause severe respiratory and systemic infections in birds and several mammalian species. The recent global outbreak of the H5N1 clade 2.3.4.4b spread in wild and domestic birds is now considered to be a panzoonosis. Spillover events in dairy cattle farms in the U.S. have highlighted the urgent need for effective antiviral therapies, especially in view of human infections. This study investigates the selective MEK1/2 inhibitor zapnometinib (ZMN) as a potential antiviral agent against HPAIVs. Our in vitro experiments demonstrate that ZMN significantly impairs viral replication across multiple HPAIV strains, including H5N1 clade 2.3.4.4b in cell lines and primary bronchial epithelial cells. The mechanism of action is based on the nuclear retention of newly produced viral ribonucleoprotein complexes (vRNP), when the MEK/ERK/RSK1 kinase cascade is inhibited. We furthermore could show, that ZMN not only acts antiviral in a standalone treatment but has synergistic potential when used in combination with direct acting antivirals like oseltamivir or baloxavir. Therefore, ZMN treatment offers a promising strategy for future antiviral development.