ZIKV reemerged in recent years, causing outbreaks in many parts of the world. Alarmingly, ZIKV infection has been associated with neurological complications such as Guillain-Barré syndrome (GBS) in adults and congenital fetal growth-associated anomalies in newborns. Host peripheral immune cells are one of the first to interact with the virus upon successful transmission from an infected female Aedes mosquito. However, little is known about the role of these immune cells during infection. In this work, the immune responses of monocytes, known target cells of ZIKV infection, were investigated by high-density transcriptomics. The analysis saw a robust immune response being elicited. Importantly, it also divulged that monocytes prime NK cell activities during virus infection. Removal of monocytes during the infection changed the immune milieu, which in turn reduced NK cell stimulation. This study provides valuable insights into the pathobiology of the virus and allows for the possibility of designing novel targeted therapeutics.