The incidence of orthoflavivirus infections is on the rise, yet effective antivirals are unavailable for all members of this family. Additionally, new orthoflaviviruses are emerging, highlighting the need for antiviral strategies with a pan-flavivirus activity. In response, the Global Health Priority Box was screened, leading to the identification of a compound with pan-flavivirus activity. This hit compound demonstrated inhibition of viral replication, consistent efficacy across various cell lines, and maintained activity even at high multiplicity of infection. Importantly it has a high barrier to resistance and possibly acts through a novel mechanism of action. Due to these attributes and its favorable in vitro ADMET profile, compound MMV1791425 emerges as a promising candidate for the future development of a pan-flavivirus antiviral.