Zika virus (ZIKV), an arbovirus of the Flaviviridaefamily, has emerged as a signifi cant public healthconcern owing to its association with congenital abnormalitiesand severe neurological sequelae. Thus, there is anurgent need to develop eff ective therapeutic approaches toeffi ciently treat ZIKV infections. This study used phenotypicscreening to identify a series of 1,2,4-oxadiazole derivativesthat possess antiviral activity against ZIKV infection. Subsequently,28 new derivatives were designed, synthesized,and evaluated for this purpose. Among these compounds,4-(5-phenyl-1,2,4-oxadiazol-3-yl)-N-(pyridin-3-ylmethyl)aniline ( 5d ) had potent antiviral activity against ZIKV infections. Furthermore, a structure–activity relationship analysisindicated that a benzyl substitution on the aniline nitrogen ofthis compound improved potency while augmenting its druglikeproperties. In addition, 5d exhibited antiviral activity against various viruses of Flaviviridae family of worldwidepublic health importance, such as dengue, Japanese encephalitisand classical swine fever viruses, indicating its potentialas a lead compound for generating 1,2,4-oxadiazole derivativeswith broad-spectrum anti-fl aviviral properties.