Flaviviruses are positive sense single strand RNA viruses (+ssRNA), which include several clinically important and widespread mosquito-borne viruses such as dengue, Zika and yellow fever viruses. These viruses have a demonstrated ability to invade new environments with ease and mutate to cause increasingly severe disease symptoms, and the imminent threats of climate change and urban development have the potential to greatly alter the epidemiology of these viruses. Upon entry into a cell, flaviviruses cause a drastic rearrangement of the host cell lipid landscape, sequestering and upregulating lipid synthesis to provide substrates for increased metabolism and the formation of membranous replication complexes. Perturbing the synthesis of certain lipid classes has been demonstrated to attenuate the replication of some viruses and could therefore be a potentially effective antiviral target. Here we investigate the role and manipulation of fatty acid synthase (FASN) by West Nile and Zika viruses, and the relationship between viral replication and lipid droplet content. We used several chemical inhibitors of FASN targeting different enzymatic domains, to determine which domains and metabolites contribute to replication. We found that inhibitors, orlistat and C75, had a profound effect on replication and infectious virus production. Additionally, we found that treating with orlistat caused the induction of intracellular lipid droplets not seen with other treatments, and that exogenously adding fatty acids did not rescue the inhibitory effect or orlistat but did for c75. Collectively our data suggests that blocking this domain is attenuating viral replication via a mechanism other than reducing the bioavailability of lipids to the virus, and this is something we are currently investigating.