Despite that great effort is currently running in the direction of vaccine and drug development, limited number of therapeutics are currently approved against seasonal influenza virus. To limit the spread of the transmission of highly pathogenic influenza (HPAI) viruses including HPAI H5N8 to mammals, it is recommended to control them in their natural and intermediate reservoirs, namely domestic poultry. Herein we aim to test both Moringa oleifera extract against the reference M2-channel blocker amantadine as antivirals against the Egyptian H5N8 isolate, specifically influenza A/chicken/Egypt/Q16684C/2019 (H5N8) virus.  Interestingly, beside its high safety on MDCK cells (CC₅₀= 15.42 mg/ml), the extract shows a promising and potent antiviral activity (IC₅₀ = 0.665 µg/ml) against HPAI H5N8, while the 50% inhibitory concentration (IC₅₀) of the amantadine was 56.81 µM. Moringa oleifera extract has shown a very promising effect as an anti-influenza, which makes it worthy of further studies.