<p>Zika virus is an arbovirus transmitted to humans by mosquitoes of the <i>Aedes</i> genus and has been associated to several outbreaks over the last two decades. Given the potential of plant-based compounds in therapeutic applications, <i>Bixa orellana</i> L., Bixaceae (commonly known as "urucum"), traditionally used by indigenous communities in Brazil and other tropical regions, was investigated for its protective effect against zika virus. In this study we evaluated the cytoprotective potential of aqueous fraction of <i>B. orellana</i> leaves in zika virus-infected Vero cells. We assessed cell viability, viral replication kinetics, and lysosomal membrane stability following infection and treatment. Phytochemical analysis revealed the presence of anthocyanins, anthocyanidins, tannins, leucoanthocyanidins, and flavonoids. The aqueous fraction of <i>B. orellana</i> exhibited no cytotoxic effects and demonstrated a significant protective effect by reducing cytopathic effects induced by zika virus. Furthermore, the aqueous fraction of <i>B. orellana</i> demonstrated a strong protective activity on lysosomes, suggesting its potential to mitigate virus-induced cellular damage. These findings suggest that <i>B. orellana</i>, particularly its aqueous fraction, contains bioactive compounds capable of reducing the cytopathic effect of zika virus <i>in vitro</i>, highlighting its promise as a supportive therapeutic agent for infections caused by the ika virus and possibly other flaviviruses.</p> Graphical Abstract <p></p>