We show that ZIKV infection triggers an atypical tripartite UPR in A549 cells involving transient activation of the effectors X-box-binding protein 1, activating transcription factor 4 (ATF4), CCAAT enhancer-binding protein-homologous protein, and growth arrest and DNA damage-inducible protein 34 during early infection and sustained activation of all three UPR sensors: RNA-activated protein kinase-like endoplasmic reticulum-resident kinase (PERK), inositol-requiring kinase-1α (IRE1α), and ATF6. Here, ATF6 is linked to Zika virus infectious disease.