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Bluetongue virus (BTV) and African horse sickness virus (AHSV) are vector-borne viruses belonging to the <i>Orbivirus</i> genus, which are transmitted between hosts primarily by biting midges of the genus <i>Culicoides</i>. With recent BTV and AHSV outbreaks causing epidemics and important economy losses, there is a pressing need for efficacious drugs to treat and control the spread of these infections. The polyanionic aromatic compound aurintricarboxylic acid (ATA) has been shown to have a broad-spectrum antiviral activity. Here, we evaluated ATA as a potential antiviral compound against <i>Orbivirus</i> infections in both mammalian and insect cells. Notably, ATA was able to prevent the replication of BTV and AHSV in both cell types in a time- and concentration-dependent manner. In addition, we evaluated the effect of ATA in vivo using a mouse model of infection. ATA did not protect mice against a lethal challenge with BTV or AHSV, most probably due to the in vivo effect of ATA on immune system regulation. Overall, these results demonstrate that ATA has inhibitory activity against <i>Orbivirus</i> replication in vitro, but further in vivo analysis will be required before considering it as a potential therapy for future clinical evaluation.