Astrocytes, the most numerous and diverse cells in the central nervous system (CNS), have enhanced control of many viral infections, and are thought to restrict viral spread by mounting a rapid and robust interferon response following many viral infections, including flaviviruses. The antiviral cytokine expression profile of the astrocyte following Zika virus infection remains mostly unexplained, and this study sought to examine the astrocyte innate host response to varying zika virus strains. Astrocytes incubated with the original African strain (MR766, Uganda-1947) and an Asian lineage-derived American strain (PRVABC59, Puerto Rico-2015) at an MOI of 0.1, were downstream analysed at 6, 24 and 48-hour post-infection (hpi). Astrocytes infected with MR766 exhibited high viral load compared to PRVABC59 at 24 and 48-hpi, with IFNβ mRNA expression significantly upregulated compared to uninfected astrocytes. Similarly, MR766 infected astrocytes induced high mRNA expression levels of the ISGs, viperin and IFIT1 at 24 and 48-hpi compared to uninfected cells. This study demonstrates a lack of control of MR766 in human astrocytes despite high interferon-β and ISG responses, and published documentation of astrocyte control of other flaviviruses. In contrast, although a significant increase of PRVABC59 viral load was observed at both 24 and 48-hpi in comparison to 6-hpi, it was at least 100 fold lower in comparison to MR766 in the astrocytes, with no significant upregulation of IFNβ, Viperin or IFIT1 mRNA; indicating that astrocyte control of PRVABC59 infection possibly occurred at a very early stage of infection, and/or the antiviral mechanisms are independent of the IFNβ response. This study contributes to the understanding of different Zika virus strain dependent pathophysiological responses in astrocytes. Further astrocyte studies to assess the overall antiviral cytokine responses and related ISGs in time kinetics experiments will enrich our understanding of Zika virus pathogenesis.