Host factors that are involved in modulating cellular vesicular trafficking of virus progeny could be potential antiviral drug targets. ADP-ribosylation factors (ARFs) are GTPases that regulate intracellular vesicular transport upon GTP binding. Here we demonstrate that genetic depletion of ARF4 suppresses viral infection by multiple pathogenic RNA viruses including Zika virus (ZIKV), influenza A virus (IAV) and SARS-CoV-2. Viral infection leads to ARF4 activation and virus production is rescued upon complementation with active ARF4, but not with inactive mutants. Mechanistically, ARF4 deletion disrupts translocation of virus progeny into the Golgi complex and redirects them for lysosomal degradation, thereby blocking virus release. More importantly, peptides targeting ARF4 show therapeutic efficacy against ZIKV and IAV challenge in mice by inhibiting ARF4 activation. Our findings highlight the role of ARF4 during viral infection and its potential as a broad-spectrum antiviral target for further development.