Emerging microbe infections such as Zika virus (ZIKV) pose an increasing threat to human health. Current investigations on ZIKV replication have revealed the construction of replication compartments (RCs) and the utilization of host cellular endomembranes, without careful examination of the cytoskeletal network. Here, we investigated the function of vimentin, one of the intermediate filaments (IFs) that play a central role in basic cellular functions and diseases, in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments have drastic reorganization upon viral protein synthesis, to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetically removal of vimentin markedly reduced viral genome replication, viral protein production and infectious virions release, without interrupting viral binding and entry. Furthermore, proteomics and transcriptome screens by mass spectrometry and RNA sequencing identified intense interaction and regulation between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1 (RRBP1), an ER transmembrane protein directly binds viral RNA, can interact with vimentin, resulting in modulation of ZIKV replication. Together, our work discovered a dual role for vimentin as being not only a structural element for RCs but also an RNA-binding-regulating hub in the ZIKV infection model, unveiling another layer of the complexity between host and virus interaction.