To study how the Zika virus (ZIKV) interacts with the host unfolded pro-tein response (UPR), we undertook a kinetics study. We show that ZIKV infection trig-gers an atypical tripartite UPR in A549 cells involving transient activation of theeffectors X-box-binding protein 1, activating transcription factor 4 (ATF4), CCAATenhancer-binding protein-homologous protein, and growth arrest and DNA damage-inducible protein 34 during early infection and sustained activation of all three UPRsensors: RNA-activated protein kinase-like endoplasmic reticulum-resident kinase(PERK), inositol-requiring kinase-1a(IRE1a), and ATF6. Sustained phosphorylation ofthe eukaryotic translation initiation factor 2aand rRNA degradation coincide withhost translational shutoff, cell lysis, and virus release during late infection. We showa blunted response of the master negative regulator, the immunoglobulin heavy-chain-binding protein (BiP), by chemical UPR inducers, and we show that ZIKV sup-presses BiP transcription and translation, suggesting that it may be necessary toblunt the BiP response to sustain UPR sensor activation. The PERK inhibitorGSK2606414 alone has no effects but synergizes with the ATF6 inhibitor Ceapin-A7to inhibit early and late infection, whereas Ceapin-A7 alone inhibits late infection.Likewise, 4-phenylbutyric acid inhibits ZIKV replication by attenuating the PERK andATF6 pathways and potentiating the IRE1apathway, suggesting that ZIKV infectionis differentially and temporally regulated by different UPR arms. ZIKV infection isinhibited by pretreatment of chemical UPR inducers but is refractory to the inhibi-tory activity of chemical inducers once infection has been established, suggestingthat ZIKV has anti-UPR mechanisms that may be able to modulate and co-opt theUPR in its life cycle.