The mimicry of host proteins by viruses contributes to their ability to suppress antiviral immunity and hijack host biosynthetic machinery. Host adaptation to evade this exploitation depends on host protein functional redundancy. Non-redundant, essential host proteins have limited potential to adapt without severe consequences. Histones, which are essential for genome architecture and control of gene expression, are among the most evolutionary conserved proteins. Here we show that the capsid protein of the flavivirus yellow fever virus (YFV), mimics histone H4 and interferes with chromatin gene regulation by BRD4, a bromodomain and extraterminal domain (BET) protein. Two acetyl-lysine residues of YFV capsid are embedded in a histone-like motif that interacts with the BRD4 bromodomain, affecting gene expression and influencing YFV replication. These findings reveal histone mimicry as a strategy employed by an RNA virus that replicates in the cytosol and define convergent and distinct molecular determinants for motif recognition of the viral mimic versus histone H4.Competing Interest StatementThe authors have declared no competing interest.