Understanding pathways that might impact viral diseases outcomes is necessary for better disease management and for therapeutic development. Viruses rely on internal cell mechanisms; therefore, they must cross cell membranes during their lifecycle, creating a dependency on processes involving membrane dynamics. We found alterations in sphingolipid levels upon infection with two different enveloped RNA viruses of different genus: (i) Neuroinvasive Sindbis virus (SVNI), and (ii) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. Glucosylceramide synthase (GCS) inhibitors inhibit the replication of both SVNI and SARS-CoV-2 in-vitro. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Treatment with GCS inhibitor reduced the detrimental immune response in the brain of SVNI-infected mice, suggest a role of glycosphingolipid levels in host immune response. Our data suggest that glycosphingolipids play a major role in viral-infection and that GCS inhibitors can potentially serve as antiviral therapeutics for viral infections.